Preventives or remedies for alzheimer&#39;s disease, or amyloid protein fibril-formation inhibitors, which include a nitrogen-containing heteroaryl compound

ABSTRACT

The present invention relates to preventives or remedies for Alzheimer&#39;s disease, or to amyloid protein fibril-formation inhibitors, which include as an active ingredient a compound of general formula (I) below or a pharmacologically permitted salt thereof; and also to nitrogen-containing heteroaryl derivatives having specific substituents, or pharmacologically permitted salts thereof, which are valuable as preventives or remedies for Alzheimer&#39;s disease, or as amyloid protein fibril-formation inhibitors: 
     
       
         
         
             
             
         
       
     
     (where, R 1  and R 2  are H or alkyl; Z 1  and Z 2  are H, alkyl, alkoxy, haloalkyl or halogeno; Z 3  is alkoxy, SH, alkylthio, NH 2 , mono- or di-alkylamino, OH or halogeno; Z 4  and Z 5  are H or halogeno; and A is 4,6-pyrimidine-1,3-diyl, 1,3,5-triazine-2,6-diyl, etc).

TECHNICAL FIELD

The present invention relates to preventives or remedies for Alzheimer'sdisease and to amyloid protein fibril-formation inhibitors which includeat least one nitrogen-containing heteroaryl compound orphysiologically-permitted salt thereof as an active ingredient.

Furthermore, the present invention also relates to nitrogen-containingheteroaryl derivatives with specified substituents which are valuable aspreventives or remedies for Alzheimer's disease, or as amyloid proteinfibril-formation inhibitors.

TECHNICAL BACKGROUND

β-Amyloid protein (hereinafter referred to as Aβ) is a major structuralcomponent of the senile plaques strikingly present in the brains ofpatients with Alzheimer's disease, and it is an insoluble peptidecomprising 39 to 43 amino acids. It is produced by enzymic cleavage fromβ-amyloid protein precursor protein.

From recent detailed pathological research into the brains of patientswith Alzheimer's disease it is reported that, in the process of theoccurrence of dementia, first of all there is a build-up of Aβ withinthe brain of the patient, which triggers the formation of senileplaques, and after the passage of a considerable number of years thereoccurs neurofibrillary degeneration followed by neuronal degenerativeloss [Ann. Rev. Neurosci., Vol. 12, 463 (1989)]

Furthermore, it is reported that Aβ which comprises 40 amino acids(Aβ1-40) and its active central portion peptide (Aβ 25-35) causedegeneration and death of rat primary hippocampal neurons in an in vitroexperimental system and specifically lower the cellular MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide]reduction capacity [see, respectively, Science, Vol. 250, 279 (1990) andJ. Neurochem., Vol. 65, 2585 (1995)].

As examples of the cells exhibiting a lowering of the MTT reductioncapacity due to Aβ, there are foetal rat hippocampal neurons, PC12 cellsand HeLa cells, etc. Consequently, by measuring activity in inhibitingthis lowering of the MTT reduction capacity due to Aβ in such cells, itis possible to investigate substances which inhibit the damaging actionof Aβ on nerve cells.

Now, long-term potentiation (hereinafter referred to as LTP) is aphenomenon in which, by hippocampal nerve fibre electrical stimulationat high frequency for a short time, the synapse reaction strength isincreased over a prolonged period, and it is regarded as a model forlearning and memory. It is reported that, in hippocampal sections, Aβhas an LTP impairing action [J. Neurosci. Res. Vol. 60, 65 (2000), Proc.Natl. Acad. Sci. USA, Vol. 95, 6448 (1998), etc]. Furthermore, it isreported that, in a transgenic mouse overexpressing Aβ, LTP in thehippocampus is inhibited compared to normal mouse and, in a learningbehaviour test, the memory and learning capacity are lowered [Science,Vol. 274 99 (1996)].

Consequently, by investigating substances which inhibit LTP impairmentdue to Aβ in the hippocampus, it is possible to investigate substanceswhich lessen memory impairment caused by Aβ.

Aβ is regarded as at least one of the causes of the occurrence ofAlzheimer's disease, so a substance which inhibits the impairment ofnerve cells induced by Aβ would be effective as a preventive or remedyfor Alzheimer's disease.

Examples of known compounds which suppress nerve cell toxicity due to Aβare rifampicin [Biochem. Biophys. Res. Commun., Vol. 204, 76 (1994)],Congo Red [Proc. Natl. Acad. Sci. USA, Vol. 91, 12243 (1994) and AZ36041[Biol. Pharm. Bull., Vol. 18, 1750 (1995), etc.

Moreover, (−)-huperzine A is an example of a compound reported tosuppress LTP impairment in the hippocampus due to Aβ [Neurosci. Lett.Vol. 275 (3): 187-190 (1999)].

Illnesses which are characterized by the extracellular deposition invarious organs and tissues of polymerized amyloid protein which adopts aspecific fibrillar structure are generally classified as amyloidosis.The protein from which this amyloid is composed is, for example, inAlzheimer's disease, Aβ which is deposited in the brain; in type 2diabetes, it is amylin which is deposited in the pancreas; in familialamyloid neuropathy, it is serum prealbumin (transthyretin) which isdeposited in the peripheral nerves; it is immunoglobulin lightchain-derived AL protein in the case of amyloidosis accompanying primaryand multiple myeloma; and it is AA protein in the case of secondaryamyloidosis, etc. [See, for example, Sipe, J. D., Annu. Rev. Biochem.,Vol. 61, 947-97 (1992), etc.]

The fact that the amyloid protein in the course of fibril-formationproduces a β-sheet structure is known to be a characteristic common tomany amyloid proteins. [See, for example, Sipe, J. D., Annu. Rev.Biochem., Vol. 61, 947-97 (1992), etc.]

Aβ is a typical amyloid protein, and it accumulates in the brains ofAlzheimer's disease patients, forming senile plaques. Within the senileplaques, a β-sheet structure is adopted and fibril formation occurs, andthere is known to be characteristic staining by dyes such as thioflavinand Congo red which denote a fibrillar structure. Furthermore, it isknown that with the adoption of the β-sheet structure and fibrilformation, Aβ shows toxicity to cultured nerve cells [Pike, C. J. et al,J. Neurosci. Vol. 13, 1676-1687 (1993)]

It is also known that the amylin, which is the main structural componentof the amyloid protein deposited in the pancreas in type 2 diabetes,adopts a β-sheet structure and forms fibrils, which show toxicity topancreatic β-cells [Lorenzo, A. et al, Nature, Vol. 368, 756-760(1994)].

It is reported that amyloid proteins such as Aβ and amylin both exhibitcytotoxicity by adopting a β-sheet structure and forming fibrils, and bylowering the cell MTT reduction capacity. Consequently, it is thoughtthat compounds which inhibit this fibril formation by amyloid proteinslike Aβ and amylin would inhibit their cell toxicity. Furthermore, sincethe mechanism of such manifestation of cytotoxicity is common to anumber of amyloid proteins, it is believed that drugs which inhibit thecytotoxicity of certain amyloid proteins and suppress fibril-formationcould also inhibit cytotoxicity and fibril-formation in other amyloidproteins.

Thus, as well as Alzheimer's disease and type 2 diabetes, by suppressingfibril-formation of amyloid protein this will be effective as apreventive or remedy for, for example, immunoglobulinic amyloidosis,reactive amyloidosis, familial amyloidosis, dialysis-relatedamyloidosis, senile amyloidosis, cerebrovascular amyloidosis, hereditarycerebral hemorrhage with amyloidosis, Creutzfeldt-Jakob disease, bovinespongiform encephalitis (BSE), scrapie, medullary carcinoma of thethyroid, insulinoma, localized atrial amyloid, amyloidosis cutis,localized nodular amyloidosis and other types of amyloidosis, preferablyfor Alzheimer's disease, type 2 diabetes, dialysis-related amyloidosis,familial amyloidosis, Creutzfeldt-Jakob disease and BSE, and inparticular for Alzheimer's disease or type 2 diabetes.

Known examples of compounds which inhibit amyloid proteinfibril-formation include variant peptide (WO96/28471),imino-aza-anthracyclinone derivatives derived from anthrazalone(WO98/32754), thionaphthalene derivatives with a specific structure(JP-A-9-95444) and isochroman compounds (JP-A-2000-198781). As compoundswhich inhibit fibril-formation by Aβ in particular from amongst theamyloid proteins, there are known iAβ5 [Nat. Med., Vol. 4, 822-826(1998)], and PTI-00703 [Neurobiol. Aging, Vol. 19 (Suppl 4) 1070 (1998).However, these compounds have a structure which is completely differentfrom the nitrogen-containing heteroaryl compounds which are theeffective component of the amyloid protein fibril-formation inhibitorsof the present invention.

With regard to nitrogen-containing heteroaryls,3-[[4-[(2-fluoro-5-methylphenyl)amino]-2-pyrimidinyl]amino]-phenol and4-[[6-[(2,5-dichlorophenyl)amino]-4-pyrimidinyl]amino]-phenol aredisclosed as having an anticancer action (WO00/12485, WO00/12486, etc),and the analogous 4,6-dianilino-pyrimidine derivatives are alsodisclosed as having an anticancer action (Japanese Patent Publication(PTC) No. 9-506363). Moreover,4,4′-[(6-methyl-2,4-pyrimidinediyl)diimino]bisphenol,4,4′-[(6-amino-1,3,5-triazine-2,4-diyl)diimino]bisphenol and4,4′-[2,4-pyrimidinediyldiimino]bisphenol are disclosed as having anantibacterial action or anti-HIV action [J. Indian Chem. Soc. Vol. 58[5], 512-13 (1981), Acta Cienc. Indica. Chem. Vol. 11[1], 66-70 (1985),J. Med. Chem. Vol. 9(3), 423-4, (1966), WO99/36410, WO99/50250].

Moreover, it has been disclosed that triazine derivatives with a4-position derivative have an impeding action for kinase which is anenzyme catalysing the reaction to produce ATP by transfer of aphosphoryl group within the cell, and are valuable in the treatment ofAlzheimer's disease, etc (WO01/25220).

DISCLOSURE OF THE INVENTION

The present inventors have carried out a painstaking study with theobjective of developing preventives or remedies for Alzheimer's diseasewhich have powerful activity and are highly safe, and they havediscovered that nitrogen-containing heteroaryl compounds have anoutstanding action in inhibiting the lowering of MTT reduction capacityand in inhibiting long-term potentiation impairment in the hippocampus,and are useful as preventives or remedies for Alzheimer's disease. Thepresent invention has been perfected based on this discovery.

Furthermore, the present inventors have also carried out a painstakingstudy with the objective of developing highly active and highly safedrugs which can suppress amyloid protein fibril-formation and cansuppress cytotoxicity brought about by the amyloid protein, and theyhave discovered that nitrogen-containing heteroaryl compounds have anoutstanding inhibitory action in terms of amyloid proteinfibril-formation, and also have a fibrillar amyloid protein breakdownaction and are valuable as preventives or remedies for amyloidosis, forexample Alzheimer's disease and type 2 diabetes. The present inventionhas also been perfected based on this discovery.

This invention provides preventives or remedies for Alzheimer's disease,or amyloid protein fibril-formation inhibitors, which include at leastone nitrogen-containing heteroaryl compound, or pharmacologicallypermitted salt thereof, as an active ingredient.

It also provides nitrogen-containing heteroaryl derivatives whichpossess specified groups.

Specifically, the nitrogen-containing heteroaryl compounds which are anactive ingredient of the Alzheimer's disease preventives or remedies, orof the amyloid protein fibril-formation inhibitors, of the presentinvention, have the following general formula

In this formula,

R¹ and R² each independently represent a hydrogen atom or a C₁₋₆ alkylgroup,Z¹ and Z² each independently represent a hydrogen atom, C₁₋₆ alkylgroup, C₁₋₆ alkoxy group, halo-C₁₋₆ alkyl group or halogen atom,Z³ represents a C₁₋₆ alkoxy group, mercapto group, C₁₋₆ alkylthio group,amino group, mono- or di-C₁₋₆ alkylamino group, hydroxy group or halogenatom,Z⁴ and Z⁵ each independently represent a hydrogen atom or halogen atom,andA represents a group of formula (II) to (VI) below.

In formulae (II) to (VI) above,

R³ represents a hydrogen atom, C₁₋₆ alkyl group, C₁₋₆ alkoxy group,mercapto group, C₁₋₆ alkylthio group, amino group, mono- or di-C₁₋₆alkylamino group or hydroxy group,R⁴ represents a hydrogen atom or nitro group,R⁵ represents a hydrogen atom or C₁₋₆ alkyl group,R⁶ represents a hydrogen atom, C₁₋₆ alkyl group, C₁₋₆ alkoxy group,mercapto group, C₁₋₆ alkylthio group, amino group, mono- or di-C₁₋₆alkylamino group or hydroxy group,R⁷ and R⁸ each independently represent a hydrogen atom, C₁₋₆ alkylgroup, C₁₋₆ alkoxy group, mercapto group, C₁₋₆ alkylthio group, aminogroup or mono- or di-C₁₋₆ alkylamino group,R⁹ represents a C₁₋₆ alkyl group, C₁₋₆ alkoxy group, mercapto group,C₁₋₆ alkylthio group, amino group, mono- or di-C₁₋₆ alkylamino group orhydroxy group, andR¹⁰ and R¹¹ each independently represent a hydrogen atom, C₁₋₆ alkylgroup, C₁₋₆ alkoxy group, C₁₋₆ alkylthio group, or mono- or di-C₁₋₆alkylamino group.

Furthermore, amongst the compounds (I), the nitrogen-containingheteroaryl derivatives of the following general formula (VII) below

or general formula (VIII) below

are novel compounds.

In the above formulae, R¹, R², R³, Z¹, Z², Z⁴, Z⁵ and A have the samemeanings as above, and Z⁶ represents a C₁-C₆ alkoxy group or a halogenatom.

The “C₁-C₆ alkyl group” denoted by R¹, R², R³, R⁴, R⁵, R⁶R⁸, R⁹, R¹⁰,R¹¹, Z¹ and Z², or the C₁-C₆ alkyl portion of the “C₁-C₆ alkoxy group”denoted by R³, R⁷, R⁸, R⁹, Z¹, Z², Z³ and Z⁶ may be, for example, amethyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl,pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl or 1,2,2-trimethylpropyl group.Excepting the alkyl group and the alkyl portion of the alkoxy group inthe definitions of R¹, R², R³, R⁹, R¹⁰ and R¹¹, and the alkyl portion ofthe alkoxy group in the definitions of R⁶ and Z³, it is preferably aC₁₋₄ alkyl group, more preferably a methyl or ethyl group, and inparticular a methyl group.

The alkyl group and the alkyl portion of the alkoxy {sic} group in thedefinitions of R¹ and R² are preferably a methyl or ethyl group.

The alkyl group in the definition of R³ is preferably a C₁₋₅ alkylgroup, more preferably a C₁₋₄ alkyl group, and still more preferably anethyl, propyl or isopropyl group. The alkyl portion of the alkoxy groupin the definition of R³ is preferably a C₁₋₄ alkyl group and morepreferably a C₁₋₃ alkyl group.

The alkyl portion of the alkoxy group in the definition of R⁶ ispreferably a C₁₋₃ alkyl group, and more preferably a methyl or ethylgroup.

The alkyl group in the definition of R⁹ is preferably a C₁₋₅ alkylgroup, more preferably a C₂₋₄ alkyl group and still more preferably anethyl, propyl, isobutyl, s-butyl or t-butyl group. The alkyl portion ofthe alkoxy group in the definition of R⁹ is preferably a C₁₋₄ alkylgroup, more preferably a methyl, ethyl or butyl group, and in particulara butyl group.

The alkyl group and the alkyl portion of the alkoxy group in thedefinitions of R¹⁰ and R¹¹ are preferably a C₁₋₃ alkyl group.

The alkyl portion of the alkoxy group in the definition of Z³ ispreferably a C₁₋₃ alkyl group.

The “halogen atom” in the definitions of Z¹, Z², Z³, Z⁴, Z⁵ and Z⁶ isfor example a fluorine, chlorine, bromine or iodine atom, preferably afluorine or chlorine atom, and in particular a chlorine atom.

The C₁₋₆ alkyl portion of the “halo-C₁₋₆ alkyl group” in the definitionsof Z¹ and Z² is the same as in the case of the C₁₋₆ alkyl group above,and the halogen portion is the same as the halogen atom above. Examplesare the fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl,1,1-difluoroethyl, 1,2-difluoroethyl, 1-chloroethyl, 2-chloroethyl,1,1-dichloroethyl and 1,2-dichloroethyl group, with the fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, 1-fluoroethyl and 1-chloroethyl group being preferred,and the trifluoromethyl group further preferred.

The C₁₋₆ alkyl portion of the “C₁₋₆ alkylthio group” in the definitionsof R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and Z³ is the same as the C₁₋₆ alkylgroup above, and examples are methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, s-butylthio and t-butylthio.

Excluding the alkyl portion of the thioalkyl group in the definitions ofR³, R⁶, R¹⁰, R¹¹ and Z³, a C₁₋₄ alkylthio is preferred, more preferablythe methylthio or ethylthio group, and in particular the methylthiogroup.

With regard to the alkyl portion of the thioalkyl group in thedefinitions of R³, R⁶, R¹⁰, R¹¹ and Z³ this is preferably a C₁₋₃ alkylgroup, with the methylthio group being particularly preferred.

The C₁₋₆ alkyl portion of the “mono- or di-C₁₋₆ alkylamino group” in thedefinitions of R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and Z³ is the same as theC₁₋₆ alkyl group above, examples being the methylamino, ethylamino,propylamino, dimethylamino, methylethylamino, methylpropylamino,diethylamino, ethylpropylamino and dipropylamino groups. Except in thecase of R³ and R⁹, the methylamino, ethylamino or dimethylamino group ispreferred, with the methylamino group particularly preferred. Withregard to the mono- or di-alkylamino group in the definitions of R³ andR⁹, a mono- or di-C₁₋₃ alkylamino group is preferred, and methylamino ordimethylamino is further preferred.

Z³ is preferably a C₁₋₄ alkoxy group, C₁₋₄ alkylthio group or hydroxygroup, more preferably a C₁₋₂ alkoxy group, C₁₋₂ alkylthio group orhydroxy group, with a hydroxy group particularly preferred.

In the case of the compounds of the present invention represented bygeneral formula (I) or (VII) above, the following preferred compoundscan be cited.

1) The compounds where R¹ and R² are each independently a hydrogen atomor a C₁₋₂ alkyl group,2) The compounds where R¹ and R² are hydrogen atoms,3) The compounds where A is a group represented by formula (II) (whereR³ is a hydrogen atom, C₁₋₅ alkyl, C₁₋₃ alkylthio or mono- or di-C₁₋₃alkylamino group, and R⁴ is a hydrogen atom or nitro group), a grouprepresented by formula (III) (where R⁵ and R⁶ are each independently ahydrogen atom or C₁₋₂ alkyl group), a group of formula (IV) (where R⁷and R⁸ are each independently a hydrogen atom or C₁₋₂ alkyl group), agroup of formula (V) (where R⁹ is a C₁₋₅ alkyl, C₁₋₄ alkoxy or a C₁₋₄alkylthio group), or a group of formula (VI) (where R¹⁰ and R¹¹ are eachindependently a hydrogen atom or C₁₋₃ alkyl group),4) The compounds where A is a group of formula (II) (where R³ is ahydrogen atom, C₁₋₅ alkyl, C₁₋₃ alkylthio or mono- or di-C₁₋₃ alkylaminogroup, and R⁴ is a hydrogen atom or nitro group), a group of formula(III) (where R⁵ is a hydrogen atom and R⁶ is a methyl or ethyl group), agroup of formula (IV) (where R⁷ and R⁸ are hydrogen atoms), a group offormula (V) (where R⁹ is a C₁₋₅ alkyl, C₁₋₄ alkoxy or C₁₋₄ alkylthiogroup), or a group of formula (VI) (where R¹⁰ and R¹¹ are hydrogenatoms),5) The compounds where A is a group of formula (II) (where R³ is ahydrogen atom, C₁₋₄ alkyl or amino group, and R⁴ is a hydrogen atom ornitro group) or a group of formula (V) (where R⁹ is a C₂₋₄ alkyl or abutoxy group),6) The compounds where A is a group of formula (II) (where R³ is anethyl, propyl, isopropyl or amino group and R⁴ is a hydrogen atom, or R³is a hydrogen atom and R⁴ is a nitro group) or a group of formula (V)(where R⁹ is a C₂₋₄ alkyl group),

7) The compounds where Z¹ and Z² are each independently a hydrogen atomor para-position fluorine atom, chlorine atom or C₁₋₂ alkyl group,

-   -   Z³ is a meta-position hydroxy group (in the case of compound        (I)), or the hydroxy group on the phenyl ring to which Z¹ is        bonded is in the meta-position (in the case of compound (VII))        and    -   Z⁴ and Z⁵ are hydrogen atoms,

8) The compounds where Z¹ and Z² are each a hydrogen atom orpara-position methyl group,

-   -   Z³ is a meta-position hydroxy group (in the case of compound        (I), or the hydroxy group on the phenyl ring to which Z¹ is        bonded is in the meta-position (in the case of compound (VII)),        and    -   Z⁴ and Z⁵ are hydrogen atoms.

Taking these together, for example combinations of 2), 3) to 6) and 8)are preferred. Amongst these combinations, the combination of 2), 6) and8) is further preferred.

Moreover, in the case of the compounds (VIII), there can be cited

1) the compounds where R¹ and R² are each independently a hydrogen atomor C₁₋₂ alkyl group,

2) the compounds where R¹ and R² are hydrogen atoms,

3) the compounds where R³ is a hydrogen atom, C₁₋₅ alkyl, C₁₋₃alkylthio, mono- or di-C₁₋₃ alkylamino group or amino group,

4) the compounds where R³ is a hydrogen atom, C₁₋₄ alkyl or amino group,

5) the compounds where R³ is an ethyl, propyl, isopropyl or amino group,

6) the compounds where Z⁶ is a C₁₋₄ alkoxy group, fluorine atom orchlorine atom, and

7) the compounds where Z⁶ is a methoxy group, ethoxy group or chlorineatom.

Taking these together, for example combinations of 2), 3) to 5) and 7)are preferred. Amongst these combinations, the combination of 2), 5) and7) is further preferred.

The compounds of the present invention of general formula (I), (VII) or(VIII) possess within the same molecule a phenolic hydroxy group, whichis a weakly acidic group, and an amino group or alkylamino group, etc,which is a weakly basic group, so they form physiologically permittedsalts when reacted with a comparatively strong base or acid. Examples ofsuch salts are the salts with a base, such as alkali metal salts likethe lithium salt, sodium salt and potassium salt, alkaline earth metalsalts like the magnesium salt, calcium salt and barium salt, and aminoacid salts like the glycine salt, lysine salt, arginine salt, ornithinesalt, glutamic acid salt and aspartic acid salt. The alkali metal saltsare preferred (in particular the sodium salt).

Furthermore, examples of the salts with an acid are mineral acid saltslike hydrohalide salts such as the hydrochloride, hydrobromide andhydroiodide, the nitrate, perchlorate, sulphate, phosphate andcarbonate, sulphonic acid salts like the methanesulphonate,trifluoromethanesulphonate, ethanesulphonate, benzene-sulphonate andtoluenesulphonate, and carboxylic acid salts such as the acetate,fumarate and maleate. The hydrochloride, nitrate, sulphate and phosphateare preferred.

Moreover, where the compounds of the present invention and theirpharmacologically permitted salts form solvates (such as hydrates), thenthese too are included within the scope of the invention.

Tables 1 to 5 below give specific examples of preferred compoundsrepresented by aforesaid general formulae (I), (VII) or (VIII). Thecompounds shown in Tables 1 to 5 have the formulae denoted by (1) to (5)respectively.

With regard to the abbreviations employed below, Me means the methylgroup, Et means the ethyl group, Pr means the propyl group, iPr meansthe isopropyl group, Bu means the butyl group, iBu means the isobutylgroup, sBu means the s-butyl group, tBu means the t-butyl group, Pnmeans the pentyl group and Hx means the hexyl group.

The compounds of the following general formula

[where R^(x), R^(y) and R^(z) are the same or different, and eachrepresent a hydrogen atom or a C₁₋₄ alkyl group (preferably R^(x), R^(y)and R^(z) are the same or different, and each represent a hydrogen atomor a methyl group; more preferably, R^(x), R^(y) and R^(z) are methylgroups), and n is 1 or 2 (preferably 2)] are known compounds (see, forexample, JP-A-5-32654), and possess an outstanding action in inhibitinga lowering of the MTT reduction capacity and in inhibiting LTPimpairment in the hippocampus, and they are valuable as Alzheimer'sdisease preventives or remedies.

TABLE 1 (1)

Exemplified Compound No. R¹ R² R³ R⁴ Z¹ Z² Z³ Z⁴ Z⁵ 1-1  H H H H H H3-OH H H 1-2  H H Me H H H 3-OH H H 1-3  H H Et H H H 3-OH H H 1-4  H HPr H H H 3-OH H H 1-5  H H iPr H H H 3-OH H H 1-6  H H Bu H H H 3-OH H H1-7  H H iBu H H H 3-OH H H 1-8  H H sBu H H H 3-OH H H 1-9  H H tBu H HH 3-OH H H 1-10  H H OH H H H 3-OH H H 1-11  H H OMe H H H 3-OH H H1-12  H H OEt H H H 3-OH H H 1-13  H H OPr H H H 3-OH H H 1-14  H H OiPrH H H 3-OH H H 1-15  H H OBu H H H 3-OH H H 1-16  H H OiBu H H H 3-OH HH 1-17  H H OsBu H H H 3-OH H H 1-18  H H OtBu H H H 3-OH H H 1-19  H HSH H H H 3-OH H H 1-20  H H SMe H H H 3-OH H H 1-21  H H SEt H H H 3-OHH H 1-22  H H NH₂ H H H 3-OH H H 1-23  H H NHMe H H H 3-OH H H 1-24  H HNMe₂ H H H 3-OH H H 1-25  H H NMeEt H H H 3-OH H H 1-26  H H NEt₂ H H H3-OH H H 1-27  H Me H H H H 3-OH H H 1-28  Me Me H H H H 3-OH H H 1-29 H Me Me H H H 3-OH H H 1-30  H Et Me H H H 3-OH H H 1-31  Me Me Me H H H3-OH H H 1-32  H Me Et H H H 3-OH H H 1-33  H Et Et H H H 3-OH H H 1-34 Me Me Et H H H 3-OH H H 1-35  Et Et Et H H H 3-OH H H 1-36  H Me Pr H HH 3-OH H H 1-37  H Et Pr H H H 3-OH H H 1-38  Me Me Pr H H H 3-OH H H1-39  Et Et Pr H H H 3-OH H H 1-40  H Me iPr H H H 3-OH H H 1-41  H EtiPr H H H 3-OH H H 1-42  Me Me iPr H H H 3-OH H H 1-43  Et Et iPr H H H3-OH H H 1-44  H Me Bu H H H 3-OH H H 1-45  H Et Bu H H H 3-OH H H 1-46 Me Me Bu H H H 3-OH H H 1-47  Et Et Bu H H H 3-OH H H 1-48  H Me iBu H HH 3-OH H H 1-49  Me Me iBu H H H 3-OH H H 1-50  H Me sBu H H H 3-OH H H1-51  Me Me sBu H H H 3-OH H H 1-52  H Me tBu H H H 3-OH H H 1-53  Me MetBu H H H 3-OH H H 1-54  H Me OH H H H 3-OH H H 1-55  Me Me OH H H H3-OH H H 1-56  H Me OMe H H H 3-OH H H 1-57  Me Me OMe H H H 3-OH H H1-58  H Me OEt H H H 3-OH H H 1-59  Me Me OEt H H H 3-OH H H 1-60  H MeOPr H H H 3-OH H H 1-61  Me Me OPr H H H 3-OH H H 1-62  H Me OiPr H H H3-OH H H 1-63  Me Me OiPr H H H 3-OH H H 1-64  H Me SH H H H 3-OH H H1-65  H Et SH H H H 3-OH H H 1-66  Me Me SH H H H 3-OH H H 1-67  Et EtSH H H H 3-OH H H 1-68  H Me SMe H H H 3-OH H H 1-69  H Et SMe H H H3-OH H H 1-70  Me Me SMe H H H 3-OH H H 1-71  Et Et SMe H H H 3-OH H H1-72  H Me SEt H H H 3-OH H H 1-73  Me Me SEt H H H 3-OH H H 1-74  H MeNH₂ H H H 3-OH H H 1-75  H Et NH₂ H H H 3-OH H H 1-76  Me Me NH₂ H H H3-OH H H 1-77  Et Et NH₂ H H H 3-OH H H 1-78  H Me NHMe H H H 3-OH H H1-79  Me Me NHMe H H H 3-OH H H 1-80  H Me NMe₂ H H H 3-OH H H 1-81  MeMe NMe₂ H H H 3-OH H H 1-82  H Me NMeEt H H H 3-OH H H 1-83  Me Me NMeEtH H H 3-OH H H 1-84  H Me NEt₂ H H H 3-OH H H 1-85  Me Me NEt₂ H H H3-OH H H 1-86  H H H H 2-Me 2-Me 3-OH H H 1-87  H H H H 4-Me 4-Me 3-OH HH 1-88  H H H H 4-OMe 4-OMe 3-OH H H 1-89  H H Me H 4-Me 4-Me 3-OH H H1-90  H H Me H 5-CF₃ 5-CF₃ 3-OH H H 1-91  H H Et H 4-Me 4-Me 3-OH H H1-92  H H Pr H 4-Me 4-Me 3-OH H H 1-93  H H iPr H 4-Me 4-Me 3-OH H H1-94  H H Bu H 4-Me 4-Me 3-OH H H 1-95  H H iBu H 4-Me 4-Me 3-OH H H1-96  H H sBu H 4-Me 4-Me 3-OH H H 1-97  H H tBu H 4-Me 4-Me 3-OH H H1-98  H H OH H 4-Me 4-Me 3-OH H H 1-99  H H SH H 4-Me 4-Me 3-OH H H1-100 H H SMe H 4-Me 4-Me 3-OH H H 1-101 H H SEt H 4-Me 4-Me 3-OH H H1-102 H H NH₂ H 4-Me 4-Me 3-OH H H 1-103 H H NHMe H 4-Me 4-Me 3-OH H H1-104 H H NMe₂ H 4-Me 4-Me 3-OH H H 1-105 H H NMeEt H 4-Me 4-Me 3-OH H H1-106 H H NEt₂ H 4-Me 4-Me 3-OH H H 1-107 H H H H H H 3-OMe H H 1-108 HH Me H H H 3-OMe H H 1-109 H H Et H H H 3-OMe H H 1-110 H H Pr H H H3-OMe H H 1-111 H H iPr H H H 3-OMe H H 1-112 H H Bu H H H 3-OMe H H1-113 H H OH H H H 3-OMe H H 1-114 H H H H H H 3-OEt H H 1-115 H H Me HH H 3-OEt H H 1-116 H H Et H H H 3-OEt H H 1-117 H H Pr H H H 3-OEt H H1-118 H H iPr H H H 3-OEt H H 1-119 H H Bu H H H 3-OEt H H 1-120 H H H HH H 3-OPr H H 1-121 H H Me H H H 3-OPr H H 1-122 H H Et H H H 3-OPr H H1-123 H H Pr H H H 3-OPr H H 1-124 H H iPr H H H 3-OPr H H 1-125 H H BuH H H 3-OPr H H 1-126 H H OH H H H 3-OPr H H 1-127 H H H H H H 3-SH H H1-128 H H Me H H H 3-SH H H 1-129 H H Et H H H 3-SH H H 1-130 H H Pr H HH 3-SH H H 1-131 H H iPr H H H 3-SH H H 1-132 H H Bu H H H 3-SH H H1-133 H H OH H H H 3-SH H H 1-134 H H H H H H 3-SMe H H 1-135 H H Me H HH 3-SMe H H 1-136 H H Et H H H 3-SMe H H 1-137 H H Pr H H H 3-SMe H H1-138 H H iPr H H H 3-SMe H H 1-139 H H Bu H H H 3-SMe H H 1-140 H H OHH H H 3-SMe H H 1-141 H H Et H H H 3-SEt H H 1-142 H H Pr H H H 3-SEt HH 1-143 H H OH H H H 3-SEt H H 1-144 H H Et H H H 3-SPr H H 1-145 H H PrH H H 3-SPr H H 1-146 H H OH H H H 3-SPr H H 1-147 H H H H H H 3-NH₂ H H1-148 H H Me H H H 3-NH₂ H H 1-149 H H Et H H H 3-NH₂ H H 1-150 H H Pr HH H 3-NH₂ H H 1-151 H H OH H H H 3-NH₂ H H 1-152 H H Et H H H 3-NHMe H H1-153 H H Pr H H H 3-NHMe H H 1-154 H H OH H H H 3-NHMe H H 1-155 H H EtH H H 3-NHEt H H 1-156 H H Pr H H H 3-NHEt H H 1-157 H H OH H H H 3-NHEtH H 1-158 H H H H H H 3-F H H 1-159 H H H H H H 3-Cl H H 1-160 H H Me HH H 3-F H H 1-161 H H Me H H H 3-Cl H H 1-162 H H Pr H H H 3-F H H 1-163H H Pr H H H 3-Cl H H 1-164 H H iPr H H H 3-F H H 1-165 H H iPr H H H3-Cl H H 1-166 H H Bu H H H 3-F H H 1-167 H H Bu H H H 3-Cl H H 1-168 HH OH H H H 3-Cl H H 1-169 H H H H 4-F 4-F 3-OH 6-F 6-F 1-170 H H H H4-Cl 4-Cl 3-OH 6-Cl 6-Cl 1-171 H H Me H 4-F 4-F 3-OH 6-F 6-F 1-172 H HMe H 4-Cl 4-Cl 3-OH 6-Cl 6-Cl 1-173 H H H NO₂ H H 3-OH H H 1-174 H Me HNO₂ H H 3-OH H H 1-175 H Et H NO₂ H H 3-OH H H 1-176 Me Me H NO₂ H H3-OH H H 1-177 Et Et H NO₂ H H 3-OH H H 1-178 H H Me NO₂ H H 3-OH H H1-179 H H Et NO₂ H H 3-OH H H 1-180 H H Pr NO₂ H H 3-OH H H 1-181 H HiPr NO₂ H H 3-OH H H 1-182 H H Bu NO₂ H H 3-OH H H 1-183 H H OH NO₂ H H3-OH H H 1-184 H H OMe NO₂ H H 3-OH H H 1-185 H H OEt NO₂ H H 3-OH H H1-186 H H OPr NO₂ H H 3-OH H H 1-187 H H OiPr NO₂ H H 3-OH H H 1-188 H HOBu NO₂ H H 3-OH H H 1-189 H H SH NO₂ H H 3-OH H H 1-190 H H SMe NO₂ H H3-OH H H 1-191 H H SEt NO₂ H H 3-OH H H 1-192 H H NH₂ NO₂ H H 3-OH H H1-193 H H NHMe NO₂ H H 3-OH H H 1-194 H H NMe₂ NO₂ H H 3-OH H H 1-195 HH NMeEt NO₂ H H 3-OH H H 1-196 H H NEt₂ NO₂ H H 3-OH H H 1-197 H H Pn HH H 3-OH H H 1-198 H H 3-MeBu H H H 3-OH H H 1-199 H H Hx H H H 3-OH H H1-200 H H H H H H 3-NHMe H H 1-201 H H Me H H H 3-NHMe H H 1-202 H H H HH H 3-NHEt H H 1-203 H H Me H H H 3-NHEt H H 1-204 H H Et H H H 3-F H H1-205 H H Et H H H 3-Cl H H 1-206 H H SPr H H H 3-OH H H 1-207 H H SiPrH H H 3-OH H H 1-208 H Me SPr H H H 3-OH H H 1-209 H Et SPr H H H 3-OH HH 1-210 Me Me SPr H H H 3-OH H H 1-211 Et Et SPr H H H 3-OH H H 1-212 HMe SiPr H H H 3-OH H H 1-213 H Et SiPr H H H 3-OH H H 1-214 Me Me SiPr HH H 3-OH H H 1-215 Et Et SiPr H H H 3-OH H H 1-216 H H OH H H H 3-OEt HH 1-217 H H H H H H 3-OiPr H H 1-218 H H Me H H H 3-OiPr H H 1-219 H HEt H H H 3-OiPr H H 1-220 H H Pr H H H 3-OiPr H H 1-221 H H iPr H H H3-OiPr H H 1-222 H H Bu H H H 3-OiPr H H 1-223 H H OH H H H 3-OiPr H H

TABLE 2 (2)

Exemplified Compound No. R¹ R² R⁵ R⁶ Z¹ Z² Z³ Z⁴ Z⁵ 2-1  H H H H H H3-OH H H 2-2  H Me H H H H 3-OH H H 2-3  H Et H H H H 3-OH H H 2-4  MeMe H H H H 3-OH H H 2-5  Et Et H H H H 3-OH H H 2-6  H H H Me H H 3-OH HH 2-7  H Me H Me H H 3-OH H H 2-8  H Et H Me H H 3-OH H H 2-9  Me Me HMe H H 3-OH H H 2-10 Et Et H Me H H 3-OH H H 2-11 H H Me Me H H 3-OH H H2-12 H Me Me Me H H 3-OH H H 2-13 H Et Me Me H H 3-OH H H 2-14 Me Me MeMe H H 3-OH H H 2-15 Et Et Me Me H H 3-OH H H 2-16 H H Me Et H H 3-OH HH 2-17 H Me Me Et H H 3-OH H H 2-18 H Et Me Et H H 3-OH H H 2-19 Me MeMe Et H H 3-OH H H 2-20 Et Et Me Et H H 3-OH H H 2-21 H H Et Et H H 3-OHH H 2-22 H Me Et Et H H 3-OH H H 2-23 H Et Et Et H H 3-OH H H 2-24 Me MeEt Et H H 3-OH H H 2-25 Et Et Et Et H H 3-OH H H 2-26 H H H OH H H 3-OHH H 2-27 H Me H OH H H 3-OH H H 2-28 H Et H OH H H 3-OH H H 2-29 Me Me HOH H H 3-OH H H 2-30 Et Et H OH H H 3-OH H H 2-31 H H H OMe H H 3-OH H H2-32 H Me H OMe H H 3-OH H H 2-33 H Et H OMe H H 3-OH H H 2-34 Me Me HOMe H H 3-OH H H 2-35 Et Et H OMe H H 3-OH H H 2-36 H H H OEt H H 3-OH HH 2-37 H Me H OEt H H 3-OH H H 2-38 H Et H OEt H H 3-OH H H 2-39 Me Me HOEt H H 3-OH H H 2-40 Et Et H OEt H H 3-OH H H 2-41 H H H OPr H H 3-OH HH 2-42 H Me H OPr H H 3-OH H H 2-43 H Et H OPr H H 3-OH H H 2-44 Me Me HOPr H H 3-OH H H 2-45 Et Et H OPr H H 3-OH H H 2-46 H H H OiPr H H 3-OHH H 2-47 H Me H OiPr H H 3-OH H H 2-48 H Et H OiPr H H 3-OH H H 2-49 MeMe H OiPr H H 3-OH H H 2-50 Et Et H OiPr H H 3-OH H H 2-51 H H H SH H H3-OH H H 2-52 H Me H SH H H 3-OH H H 2-53 H Et H SH H H 3-OH H H 2-54 MeMe H SH H H 3-OH H H 2-55 Et Et H SH H H 3-OH H H 2-56 H H H SMe H H3-OH H H 2-57 H Me H SMe H H 3-OH H H 2-58 H Et H SMe H H 3-OH H H 2-59Me Me H SMe H H 3-OH H H 2-60 Et Et H SMe H H 3-OH H H 2-61 H H H SEt HH 3-OH H H 2-62 H Me H SEt H H 3-OH H H 2-63 H Et H SEt H H 3-OH H H2-64 Me Me H SEt H H 3-OH H H 2-65 Et Et H SEt H H 3-OH H H 2-66 H H HSPr H H 3-OH H H 2-67 H Me H SPr H H 3-OH H H 2-68 H Et H SPr H H 3-OH HH 2-69 Me Me H SPr H H 3-OH H H 2-70 Et Et H SPr H H 3-OH H H 2-71 H H HSiPr H H 3-OH H H 2-72 H Me H SiPr H H 3-OH H H 2-73 H Et H SiPr H H3-OH H H 2-74 Me Me H SiPr H H 3-OH H H 2-75 Et Et H SiPr H H 3-OH H H2-76 H H H NH₂ H H 3-OH H H 2-77 H Me H NH₂ H H 3-OH H H 2-78 H Et H NH₂H H 3-OH H H 2-79 Me Me H NH₂ H H 3-OH H H 2-80 Et Et H NH₂ H H 3-OH H H2-81 H H H NHMe H H 3-OH H H 2-82 H Me H NHMe H H 3-OH H H 2-83 H Et HNHMe H H 3-OH H H 2-84 Me Me H NHMe H H 3-OH H H 2-85 Et Et H NHMe H H3-OH H H 2-86 H H H NMe₂ H H 3-OH H H 2-87 H Me H NMe₂ H H 3-OH H H 2-88H Et H NMe₂ H H 3-OH H H 2-89 Me Me H NMe₂ H H 3-OH H H 2-90 Et Et HNMe₂ H H 3-OH H H 2-91 H H H NMeEt H H 3-OH H H 2-92 H Me H NMeEt H H3-OH H H 2-93 H Et H NMeEt H H 3-OH H H 2-94 Me Me H NMeEt H H 3-OH H H2-95 Et Et H NMeEt H H 3-OH H H 2-96 H H H NEt₂ H H 3-OH H H 2-97 H Me HNEt₂ H H 3-OH H H 2-98 H Et H NEt₂ H H 3-OH H H 2-99 Me Me H NEt₂ H H3-OH H H  2-100 Et Et H NEt₂ H H 3-OH H H  2-101 H H H H 2-Me 2-Me 3-OHH H  2-102 H H H H 4-Me 4-Me 3-OH H H  2-103 H H H Me 4-Me 4-Me 3-OH H H 2-104 H H H Et 4-Me 4-Me 3-OH H H  2-105 H H Me Me 4-Me 4-Me 3-OH H H 2-106 H H Et Et 4-Me 4-Me 3-OH H H  2-107 H H H NHEt H H 3-OH H H 2-108 H Me H NHEt H H 3-OH H H  2-109 H Et H NHEt H H 3-OH H H  2-110Me Me H NHEt H H 3-OH H H  2-111 Et Et H NHEt H H 3-OH H H

TABLE 3 (3)

Exemplified Compound Number R¹ R² R⁷ R⁸ Z¹ Z² Z³ Z⁴ Z⁵ 3-1  H H H H H H3-OH H H 3-2  H Me H H H H 3-OH H H 3-3  H Et H H H H 3-OH H H 3-4  MeMe H H H H 3-OH H H 3-5  Et Et H H H H 3-OH H H 3-6  H H Me H H H 3-OH HH 3-7  H Me Me H H H 3-OH H H 3-8  H Et Me H H H 3-OH H H 3-9  Me Me MeH H H 3-OH H H 3-10 Et Et Me H H H 3-OH H H 3-11 H H Me Me H H 3-OH H H3-12 H Me Me Me H H 3-OH H H 3-13 H Et Me Me H H 3-OH H H 3-14 Me Me MeMe H H 3-OH H H 3-15 Et Et Me Me H H 3-OH H H 3-16 H H Me Et H H 3-OH HH 3-17 H Me Me Et H H 3-OH H H 3-18 H Et Me Et H H 3-OH H H 3-19 Me MeMe Et H H 3-OH H H 3-20 Et Et Me Et H H 3-OH H H 3-21 H H Et Et H H 3-OHH H 3-22 H Me Et Et H H 3-OH H H 3-23 H Et Et Et H H 3-OH H H 3-24 Me MeEt Et H H 3-OH H H 3-25 Et Et Et Et H H 3-OH H H 3-26 H H H H 4-Me 4-Me3-OH H H 3-27 H H H Me 4-Me 4-Me 3-OH H H 3-28 H H Me Me 4-Me 4-Me 3-OHH H 3-29 H H Me Et 4-Me 4-Me 3-OH H H 3-30 H H Et Et 4-Me 4-Me 3-OH H H3-31 H H H H 4-Et 4-Et 3-OH H H 3-32 H H H Me 4-Et 4-Et 3-OH H H 3-33 HH Me Me 4-Et 4-Et 3-OH H H 3-34 H H Me Et 4-Et 4-Et 3-OH H H 3-35 H H EtEt 4-Et 4-Et 3-OH H H 3-36 H H H H H H 3-OMe H H 3-37 H H H H H H 3-OEtH H 3-38 H H H H H H 3-OPr H H 3-39 H H H H H H 3-SH H H 3-40 H H H H HH 3-SMe H H 3-41 H H H H H H 3-SEt H H 3-42 H H H H H H 3-SPr H H 3-43 HH H H H H 3-NH₂ H H 3-44 H H H H H H 3-OiPr H H

TABLE 4 (4)

Exemplified Compound No. R¹ R² R⁹ Z¹ Z² Z³ Z⁴ Z⁵ 4-1 H H Me H H 3-OH H H4-2 H Me Me H H 3-OH H H 4-3 H Et Me H H 3-OH H H 4-4 Me Me Me H H 3-OHH H 4-5 Et Et Me H H 3-OH H H 4-6 H H Et H H 3-OH H H 4-7 H Me Et H H3-OH H H 4-8 H Et Et H H 3-OH H H 4-9 Me Me Et H H 3-OH H H 4-10 Et EtEt H H 3-OH H H 4-11 H H Pr H H 3-OH H H 4-12 H Me Pr H H 3-OH H H 4-13H Et Pr H H 3-OH H H 4-14 Me Me Pr H H 3-OH H H 4-15 Et Et Pr H H 3-OH HH 4-16 H H iPr H H 3-OH H H 4-17 H Me iPr H H 3-OH H H 4-18 H Et iPr H H3-OH H H 4-19 Me Me iPr H H 3-OH H H 4-20 Et Et iPr H H 3-OH H H 4-21 HH Bu H H 3-OH H H 4-22 H Me Bu H H 3-OH H H 4-23 H Et Bu H H 3-OH H H4-24 Me Me Bu H H 3-OH H H 4-25 Et Et Bu H H 3-OH H H 4-26 H H iBu H H3-OH H H 4-27 H Me iBu H H 3-OH H H 4-28 H Et iBu H H 3-OH H H 4-29 MeMe iBu H H 3-OH H H 4-30 Et Et iBu H H 3-OH H H 4-31 H H sBu H H 3-OH HH 4-32 H Me sBu H H 3-OH H H 4-33 H Et sBu H H 3-OH H H 4-34 Me Me sBu HH 3-OH H H 4-35 Et Et sBu H H 3-OH H H 4-36 H H tBu H H 3-OH H H 4-37 HMe tBu H H 3-OH H H 4-38 H Et tBu H H 3-OH H H 4-39 Me Me tBu H H 3-OH HH 4-40 Et Et tBu H H 3-OH H H 4-41 H H Pn H H 3-OH H H 4-42 H Me Pn H H3-OH H H 4-43 H Et Pn H H 3-OH H H 4-44 Me Me Pn H H 3-OH H H 4-45 Et EtPn H H 3-OH H H 4-46 H H 3-MeBu H H 3-OH H H 4-47 H Me 3-MeBu H H 3-OH HH 4-48 H Et 3-MeBu H H 3-OH H H 4-49 Me Me 3-MeBu H H 3-OH H H 4-50 EtEt 3-MeBu H H 3-OH H H 4-51 H H Hx H H 3-OH H H 4-52 H Me Hx H H 3-OH HH 4-53 H Et Hx H H 3-OH H H 4-54 Me Me Hx H H 3-OH H H 4-55 Et Et Hx H H3-OH H H 4-56 H H OH H H 3-OH H H 4-57 H Me OH H H 3-OH H H 4-58 H Et OHH H 3-OH H H 4-59 Me Me OH H H 3-OH H H 4-60 Et Et OH H H 3-OH H H 4-61H H OMe H H 3-OH H H 4-62 H Me OMe H H 3-OH H H 4-63 H Et OMe H H 3-OH HH 4-64 Me Me OMe H H 3-OH H H 4-65 Et Et OMe H H 3-OH H H 4-66 H H OEt HH 3-OH H H 4-67 H Me OEt H H 3-OH H H 4-68 H Et OEt H H 3-OH H H 4-69 MeMe OEt H H 3-OH H H 4-70 Et Et OEt H H 3-OH H H 4-71 H H OPr H H 3-OH HH 4-72 H Me OPr H H 3-OH H H 4-73 H Et OPr H H 3-OH H H 4-74 Me Me OPr HH 3-OH H H 4-75 Et Et OPr H H 3-OH H H 4-76 H H OiPr H H 3-OH H H 4-77 HMe OiPr H H 3-OH H H 4-78 H Et OiPr H H 3-OH H H 4-79 Me Me OiPr H H3-OH H H 4-80 Et Et OiPr H H 3-OH H H 4-81 H H OBu H H 3-OH H H 4-82 HMe OBu H H 3-OH H H 4-83 H Et OBu H H 3-OH H H 4-84 Me Me OBu H H 3-OH HH 4-85 Et Et OBu H H 3-OH H H 4-86 H H OiBu H H 3-OH H H 4-87 H Me OiBuH H 3-OH H H 4-88 H Et OiBu H H 3-OH H H 4-89 Me Me OiBu H H 3-OH H H4-90 Et Et OiBu H H 3-OH H H 4-91 H H OsBu H H 3-OH H H 4-92 H Me OsBu HH 3-OH H H 4-93 H Et OsBu H H 3-OH H H 4-94 Me Me OsBu H H 3-OH H H 4-95Et Et OsBu H H 3-OH H H 4-96 H H OtBu H H 3-OH H H 4-97 H Me OtBu H H3-OH H H 4-98 H Et OtBu H H 3-OH H H 4-99 Me Me OtBu H H 3-OH H H 4-100Et Et OtBu H H 3-OH H H 4-101 H H OPn H H 3-OH H H 4-102 H Me OPn H H3-OH H H 4-103 H Et OPn H H 3-OH H H 4-104 Me Me OPn H H 3-OH H H 4-105Et Et OPn H H 3-OH H H 4-106 H H O-3-MeBu H H 3-OH H H 4-107 H MeO-3-MeBu H H 3-OH H H 4-108 H Et O-3-MeBu H H 3-OH H H 4-109 Me MeO-3-MeBu H H 3-OH H H 4-110 Et Et O-3-MeBu H H 3-OH H H 4-111 H H OHx HH 3-OH H H 4-112 H Me OHx H H 3-OH H H 4-113 H Et OHx H H 3-OH H H 4-114Me Me OHx H H 3-OH H H 4-115 Et Et OHx H H 3-OH H H 4-116 H H SH H H3-OH H H 4-117 H Me SH H H 3-OH H H 4-118 H Et SH H H 3-OH H H 4-119 MeMe SH H H 3-OH H H 4-120 Et Et SH H H 3-OH H H 4-121 H H SMe H H 3-OH HH 4-122 H Me SMe H H 3-OH H H 4-123 H Et SMe H H 3-OH H H 4-124 Me MeSMe H H 3-OH H H 4-125 Et Et SMe H H 3-OH H H 4-126 H H SEt H H 3-OH H H4-127 H Me SEt H H 3-OH H H 4-128 H Et SEt H H 3-OH H H 4-129 Me Me SEtH H 3-OH H H 4-130 Et Et SEt H H 3-OH H H 4-131 H H SPr H H 3-OH H H4-132 H Me SFr H H 3-OH H H 4-133 H Et SPr H H 3-OH H H 4-134 Me Me SPrH H 3-OH H H 4-135 Et Et SPr H H 3-OH H H 4-136 H H SiPr H H 3-OH H H4-137 H Me SiPr H H 3-OH H H 4-138 H Et SiPr H H 3-OH H H 4-139 Me MeSiPr H H 3-OH H H 4-140 Et Et SiPr H H 3-OH H H 4-141 H H SBu H H 3-OH HH 4-142 H Me SBu H H 3-OH H H 4-143 H Et SBu H H 3-OH H H 4-144 Me MeSBu H H 3-OH H H 4-145 Et Et SBu H H 3-OH H H 4-146 H H SiBu H H 3-OH HH 4-147 H Me SiBu H H 3-OH H H 4-148 H Et SiBu H H 3-OH H H 4-149 Me MeSiBu H H 3-OH H H 4-150 Et Et SiBu H H 3-OH H H 4-151 H H SsBu H H 3-OHH H 4-152 H Me SsBu H H 3-OH H H 4-153 H Et SsBu H H 3-OH H H 4-154 MeMe SsBu H H 3-OH H H 4-155 Et Et SsBu H H 3-OH H H 4-156 H H StBu H H3-OH H H 4-157 H Me StBu H H 3-OH H H 4-158 H Et StBu H H 3-OH H H 4-159Me Me StBu H H 3-OH H H 4-160 Et Et StBu H H 3-OH H H 4-161 H H SPn H H3-OH H H 4-162 H Me SPn H H 3-OH H H 4-163 H Et SPn H H 3-OH H H 4-164Me Me SPn H H 3-OH H H 4-165 Et Et SPn H H 3-OH H H 4-166 H H S-3-MeBu HH 3-OH H H 4-167 H Me S-3-MeBu H H- 3-OH H H 4-168 H Et S-3-MeBu H H3-OH H H 4-169 Me Me S-3-MeBu H H 3-OH H H 4-170 Et Et S-3-MeBu H H 3-OHH H 4-171 H H SHx H H 3-OH H H 4-172 H Me SHx H H 3-OH H H 4-173 H EtSHx H H 3-OH H H 4-174 Me Me SHx H H 3-OH H H 4-175 Et Et SHx H H 3-OH HH 4-176 H H NH₂ H H 3-OH H H 4-177 H Me NH₂ H H 3-OH H H 4-178 H Et NH₂H H 3-OH H H 4-179 Me Me NH₂ H H 3-OH H H 4-180 Et Et NH₂ H H 3-OH H H4-181 H H NHMe H H 3-OH H H 4-182 H Me NHMe H H 3-OH H H 4-183 H Et NHMeH H 3-OH H H 4-184 Me Me NHMe H H 3-OH H H 4-185 Et Et NHMe H H 3-OH H H4-186 H H NMe₂ H H 3-OH H H 4-187 H Me NMe₂ H H 3-OH H H 4-188 H Et NMe₂H H 3-OH H H 4-189 Me Me NMe₂ H H 3-OH H H 4-190 Et Et NMe₂ H H 3-OH H H4-191 H H NMeEt H H 3-OH H H 4-192 H Me NMeEt H H 3-OH H H 4-193 H EtNMeEt H H 3-OH H H 4-194 Me Me NMeEt H H 3-OH H H 4-195 Et Et NMeEt H H3-OH H H 4-196 H H NEt₂ H H 3-OH H H 4-197 H Me NEt₂ H H 3-OH H H 4-198H Et NEt₂ H H 3-OH H H 4-199 Me Me NEt₂ H H 3-OH H H 4-200 Et Et NEt₂ HH 3-OH H H 4-201 H H NEtPr H H 3-OH H H 4-202 H Me NEtPr H H 3-OH H H4-203 H Et NEtPr H H 3-OH H H 4-204 Me Me NEtPr H H 3-OH H H 4-205 Et EtNEtPr H H 3-OH H H 4-206 H H NPr₂ H H 3-OH H H 4-207 H Me NPr₂ H H 3-OHH H 4-208 H Et NPr₂ H H 3-OH H H 4-209 Me Me NPr₂ H H 3-OH H H 4-210 EtEt NPr₂ H H 3-OH H H 4-211 H H Me 4-Me 4-Me 3-OH H H 4-212 H H Et 4-Me4-Me 3-OH H H 4-213 H H Pr 4-Me 4-Me 3-OH H H 4-214 H H iPr 4-Me 4-Me3-OH H H 4-215 H H Bu 4-Me 4-Me 3-OH H H 4-216 H H iBu 4-Me 4-Me 3-OH HH 4-217 H H sBu 4-Me 4-Me 3-OH H H 4-218 H H tBu 4-Me 4-Me 3-OH H H4-219 H H Pn 4-Me 4-Me 3-OH H H 4-220 H H 3-MeBu 4-Me 4-Me 3-OH H H4-221 H H Hx 4-Me 4-Me 3-OH H H 4-222 H H OH 4-Me 4-Me 3-OH H H 4-223 HH Me H H 3-OMe H H 4-224 H Me Me H H 3-OMe H H 4-225 H Et Me H H 3-OMe HH 4-226 Me Me Me H H 3-OMe H H 4-227 Et Et Me H H 3-OMe H H 4-228 H H OHH H 3-OMe H H 4-229 H Me OH H H 3-OMe H H 4-230 H Et OH H H 3-OMe H H4-231 Me Me OH H H 3-OMe H H 4-232 Et Et OH H H 3-OMe H H 4-233 H H Me HH 3-OEt H H 4-234 H Me Me H H 3-OEt H H 4-235 H Et Me H H 3-OEt H H4-236 Me Me Me H H 3-OEt H H 4-237 Et Et Me H H 3-OEt H H 4-238 H H OH HH 3-OEt H H 4-239 H Me OH H H 3-OEt H H 4-240 H Et OH H H 3-OEt H H4-241 Me Me OH H H 3-OEt H H 4-242 Et Et OH H H 3-OEt H H 4-243 H H Me HH 3-OPr H H 4-244 H Me Me H H 3-OPr H H 4-245 H Et Me H H 3-OPr H H4-246 Me Me Me H H 3-OPr H H 4-247 Et Et Me H H 3-OPr H H 4-248 H H OH HH 3-OPr H H 4-249 H Me OH H H 3-OPr H H 4-250 H Et OH H H 3-OPr H H4-251 Me Me OH H H 3-OPr H H 4-252 Et Et OH H H 3-OPr H H 4-253 H H Me HH 3-OiPr H H 4-254 H Me Me H H 3-OiPr H H 4-255 H Et Me H H 3-OiPr H H4-256 Me Me Me H H 3-OiPr H H 4-257 Et Et Me H H 3-OiPr H H 4-258 H H OHH H 3-OiPr H H 4-259 H Me OH H H 3-OiPr H H 4-260 H Et OH H H 3-OiPr H H4-261 Me Me OH H H 3-OiPr H H 4-262 Et Et OH H H 3-OiPr H H 4-263 H H MeH H 3-SH H H 4-264 H Me Me H H 3-SH H H 4-265 H Et Me H H 3-SH H H 4-266Me Me Me H H 3-SH H H 4-267 Et Et Me H H 3-SH H H 4-268 H H OH H H 3-SHH H 4-269 H Me OH H H 3-SH H H 4-270 H Et OH H H 3-SH H H 4-271 Me Me OHH H 3-SH H H 4-272 Et Et OH H H 3-SH H H 4-273 H H Me H H 3-SMe H H4-274 H Me Me H H 3-SMe H H 4-275 H Et Me H H 3-SMe H H 4-276 Me Me Me HH 3-SMe H H 4-277 Et Et Me H H 3-SMe H H 4-278 H H OH H H 3-SMe H H4-279 H Me OH H H 3-SMe H H 4-280 H Et OH H H 3-SMe H H 4-281 Me Me OH HH 3-SMe H H 4-282 Et Et OH H H 3-SMe H H 4-283 H H Me H H 3-SEt H H4-284 H Me Me H H 3-SEt H H 4-285 H Et Me H H 3-SEt H H 4-286 Me Me Me HH 3-SEt H H 4-287 Et Et Me H H 3-SEt H H 4-288 H H OH H H 3-SEt H H4-289 H Me OH H H 3-SEt H H 4-290 H Et OH H H 3-SEt H H 4-291 Me Me OH HH 3-SEt H H 4-292 Et Et OH H H 3-SEt H H 4-293 H H Me H H 3-SPr H H4-294 H Me Me H H 3-SPr H H 4-295 H Et Me H H 3-SPr H H 4-296 Me Me Me HH 3-SPr H H 4-297 Et Et Me H H 3-SPr H H 4-298 H H OH H H 3-SPr H H4-299 H Me OH H H 3-SPr H H 4-300 H Et OH H H 3-SPr H H 4-301 Me Me OH HH 3-SPr H H 4-302 Et Et OH H H 3-SPr H H 4-303 H H Me H H 3-NH₂ H H4-304 H Me Me H H 3-NH₂ H H 4-305 H Et Me H H 3-NH₂ H H 4-306 Me Me Me HH 3-NH₂ H H 4-307 Et Et Me H H 3-NH₂ H H 4-308 H H OH H H 3-NH₂ H H4-309 H Me OH H H 3-NH₂ H H 4-310 H Et OH H H 3-NH₂ H H 4-311 Me Me OH HH 3-NH₂ H H 4-312 Et Et OH H H 3-NH₂ H H 4-313 H H Me H H 3-NHMe H H4-314 H Me Me H H 3-NHMe H H 4-315 H Et Me H H 3-NHMe H H 4-316 Me Me MeH H 3-NHMe H H 4-317 Et Et Me H H 3-NRMe H H 4-318 H H OH H H 3-NHMe H H4-319 H Me OH H H 3-NHMe H H 4-320 H Et OH H H 3-NHMe H H 4-321 Me Me OHH H 3-NHMe H H 4-322 Et Et OH H H 3-NHMe H H 4-323 H H Me H H 3-NHEt H H4-324 H Me Me H H 3-NHEt H H 4-325 H Et Me H H 3-NHEt H H 4-326 Me Me MeH H 3-NHEt H H 4-327 Et Et Me H H 3-NHEt H H 4-328 H H OH H H 3-NHEt H H4-329 H Me OH H H 3-NHEt H H 4-330 H Et OH H H 3-NHEt H H 4-331 Me Me OHH H 3-NHEt H H 4-332 Et Et OH H H 3-NHEt H H 4-333 H H Me H H 3-F H H4-334 H Me Me H H 3-F H H 4-335 H Et Me H H 3-F H H 4-336 Me Me Me H H3-F H H 4-337 Et Et Me H H 3-F H H 4-338 H H Et H H 3-F H H 4-339 H H PrH H 3-F H H 4-340 H H iPr H H 3-F H H 4-341 H H Bu H H 3-F H H 4-342 H HOH H H 3-F H H 4-343 H H Me H H 3-Cl H H 4-344 H Me Me H H 3-Cl H H4-345 H Et Me H H 3-Cl H H 4-346 Me Me Me H H 3-Cl H H 4-347 Et Et Me HH 3-Cl H H 4-348 H H Et H H 3-Cl H H 4-349 H H Pr H H 3-Cl H H 4-350 H HiPr H H 3-Cl H H 4-351 H H Bu H H 3-Cl H H 4-352 H H OH H H 3-Cl H H4-353 H H NHEt H H 3-OH H H 4-354 H Me NHEt H H 3-OH H H 4-355 H Et NHEtH H 3-OH H H 4-356 Me Me NHEt H H 3-OH H H 4-357 Et Et NHEt H H 3-OH H H4-358 H H NHPr H H 3-OH H H 4-359 H Me NHPr H H 3-OH H H 4-360 H Et NHPrH H 3-OH H H 4-361 Me Me NHPr H H 3-OH H H 4-362 Et Et NHPr H H 3-OH H H

TABLE 5 (5)

Ex- emplified Com- pound Number R¹ R² R¹⁰ R¹¹ Z¹ Z² Z³ Z⁴ Z⁵ 5-1  H H HH H H 3-OH H H 5-2  H H H Me H H 3-OH H H 5-3  H H H Et H H 3-OH H H5-4  H H Me Me H H 3-OH H H 5-5  H H Et Et H H 3-OH H H 5-6  H H Pr Pr HH 3-OH H H 5-7  H H iPr iPr H H 3-OH H H 5-8  H H Bu Bu H H 3-OH H H5-9  H H iBu iBu H H 3-OH H H 5-10 H H sBu sBu H H 3-OH H H 5-11 H H tButBu H H 3-OH H H 5-12 H H OMe OMe H H 3-OH H H 5-13 H H OEt OEt H H 3-OHH H 5-14 H H OPr OPr H H 3-OH H H 5-15 H H SMe SMe H H 3-OH H H 5-16 H HSEt SEt H H 3-OH H H 5-17 H H SPr SPr H H 3-OH H H 5-18 H H NH₂ NH₂ H H3-OH H H 5-19 H H NHMe NHMe H H 3-OH H H 5-20 H H NHEt NHEt H H 3-OH H H5-21 H H NHMe₂ NMe₂ H H 3-OH H H 5-22 H H NMeEt NMeEt H H 3-OH H H 5-23H H NEt₂ NEt₂ H H 3-OH H H 5-24 H H H H 4-Me 4-Me 3-OH H H 5-25 H H H Me4-Me 4-Me 3-OH H H 5-26 H H H Et 4-Me 4-Me 3-OH H H 5-27 H H Me Me 4-Me4-Me 3-OH H H 5-28 H H Et Et 4-Me 4-Me 3-OH H H 5-29 H H Pr Pr 4-Me 4-Me3-OH H H 5-30 H H iPr iPr 4-Me 4-Me 3-OH H H 5-31 H H Bu Bu 4-Me 4-Me3-OH H H 5-32 H H iBu iBu 4-Me 4-Me 3-OH H H 5-33 H H sBu sBu 4-Me 4-Me3-OH H H 5-34 H H tBu tBu 4-Me 4-Me 3-OH H H 5-35 H H H H 4-Et 4-Et 3-OHH H 5-36 H H H Me 4-Et 4-Et 3-OH H H 5-37 H H H Et 4-Et 4-Et 3-OH H H5-38 H H Me Me 4-Et 4-Et 3-OH H H 5-39 H H Et Et 4-Et 4-Et 3-OH H H 5-40H H Pr Pr 4-Et 4-Et 3-OH H H 5-41 H H iPr iPr 4-Et 4-Et 3-OH H H 5-42 HH Bu Bu 4-Et 4-Et 3-OH H H 5-43 H H iBu iBu 4-Et 4-Et 3-OH H H 5-44 H HsBu sBu 4-Et 4-Et 3-OH H H 5-45 H H tBu tBu 4-Et 4-Et 3-OH H H 5-46 H HH H H H 3-OMe H H 5-47 H H H Me H H 3-OMe H H 5-48 H H H H H H 3-OEt H H5-49 H H H Me H H 3-OEt H H 5-50 H H H H H H 3-OPr H H 5-51 H H H Me H H3-OPr H H 5-52 H H H H H H 3-OiPr H H 5-53 H H H Me H H 3-OiPr H H 5-54H H H H H H 3-SH H H 5-55 H H H Me H H 3-SH H H 5-56 H H H H H H 3-SMe HH 5-57 H H H Me H H 3-SMe H H 5-58 H H H H H H 3-SEt H H 5-59 H H H Me HH 3-SEt H H 5-50 H H H H H H 3-SPr H H 5-61 H H H Me H H 3-SPr H H 5-62H H H H H H 3-SiPr H H 5-63 H H H Me H H 3-SiPr H H 5-64 H H H H H H3-NH₂ H H 5-65 H H H Me H H 3-NH₂ H H 5-66 H H SiPr SiPr H H 3-OH H H

Amongst the above compounds, the preferred compounds are ExemplifiedCompound Nos

1-1˜1-27, 1-29˜1-30, 1-32, 1-36˜1-37, 1-40˜1-41, 1-56, 1-58, 1-60, 1-62,1-68˜1-69, 1-71˜1-72, 1-74˜1-75, 1-86˜1-109, 1-114˜1-116, 1-120˜1-122,1-127˜1-136, 1-147˜1-153, 1-155˜1-156, 1-158˜1-165, 1-173˜1-175,1-178˜1-183, 1-200˜1-203,2-1˜2-3, 2-6˜2-8, 2-11˜2-13, 2-16˜2-18, 2-21˜2-23, 2-31˜2-33, 2-36˜2-38,2-41˜2-43, 2-46˜2-48, 2-56˜2-58, 2-61˜2-63, 2-66 ˜2-68, 2-71˜2-73,2-76˜2-78, 2-81˜2-83, 2-86˜2-88, 2-91˜2-93, 2-96˜2-98, 2-101˜2-109,3-1˜3-3, 3-6˜3-8, 3-11˜3-13, 3-16˜3-18, 3-21˜3-23, 3-26˜3-32, 4-1˜4-3,4-6˜4-8, 4-11˜4-13, 4-16˜4-18, 4-21˜4-23, 4-26˜4-28, 4-31˜4-33,4-36˜4-38, 4-41˜4-43, 4-46˜4-48, 4-51˜4-53, 4-56 ˜4-58, 4-61˜4-63,4-66˜4-68, 4-71˜4-73, 4-76˜4-78, 4-81˜4-83, 4-85˜4-88, 4-91˜4-93,4-96˜4-98, 4-101˜4-103, 4-106˜4-108, 4-111˜4-113, 4-116˜4-118,4-121˜4-123, 4-126˜4-128, 4-131˜4-133, 4-136˜4-138, 4-141˜4-143,4-146˜4-148, 4-151˜4-153, 4-156˜4-158, 4-161˜4-163, 4-166˜4-168,4-171˜4-173, 4-176˜4-178, 4-181˜4-183, 4-186˜4-188, 4-191˜4-193,4-196˜4-198, 4-201˜4-203, 4-206˜4-208, 4-211˜4-225, 4-228˜4-230,4-233˜4-235, 4-238˜4-240, 2-243˜4-245, 4-248˜4-250, 4-253˜4-255,4-258˜4-260, 4-263˜4-265, 4-268˜4-270, 4-273˜4-275, 4-278˜4-280,4-283˜4-285, 4-288˜4-290, 4-303˜4-305, 4-308˜4-310, 4-313˜4-315,4-318˜4-320, 4-323˜4-325, 4-328˜4-330, 4-353˜4-355, 4-358˜4-360,5-1˜5-7, 5-12˜17, 5-24˜5-29, 5-35˜5-40, 5-46˜5-49, 5-54˜5-57, 5-64˜5-65and the following are further preferred:—1-1˜1-6, 1-11˜1-12, 1-20˜1-26, 1-30, 1-71, 1-87, 1-89, 1-91˜1-93,1-100˜1-106, 1-127˜1-131, 1-147˜1-150, 1-152˜1-153, 1-155˜1-156, 1-161,1-173, 1-178˜1-181,2-1, 2-6, 2-11, 2-16, 2-21, 2-31, 2-36, 2-41, 2-46, 2-56, 2-61, 2-66,2-71, 2-76, 2-81, 2-86, 2-91, 2-96, 2-102˜2-107, 3-1, 3-6, 3-11, 3-16,3-21, 3-26˜3-28, 3-31˜3-32,4-1, 4-6, 4-11, 4-16, 4-21, 4-26, 4-31, 4-36, 4-41, 4-46, 4-51, 4-56,4-61, 4-66, 4-71, 4-76, 4-81, 4-85˜4-86, 4-91, 4-96, 4-101, 4-106,4-111, 4-116, 4-121, 4-126, 4-131, 4-136, 4-141, 4-146, 4-151, 4-156,4-201, 4-206, 4-211˜4-222, 4-263, 4-303, 4-313, 4-353, 4-358, 5-1˜5-6,5-12˜5-17, 5-24˜5-29, 5-35˜5-39, 5-54˜5-55, 5-64˜5-65with the following being still further preferred:—1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-22, 1-30, 1-71, 1-161, 1-173, 2-1, 2-11,4-6, 4-11, 4-26, 4-31, 4-36, 4-81, 4-212 and 5-1in particular, the following:—

-   1-1: N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine-   1-2: 2-methyl-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine-   1-3: 2-ethyl-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine-   1-4: 2-propyl-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine-   1-5: 2-isopropyl-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine-   1-6: 2-butyl-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine-   1-22: 2-amino-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine-   1-173: N,N′-bis(3-hydroxyphenyl)-5-nitropyrimidine-4,6-diamine-   2-1: N,N′-bis(3-hydroxyphenyl)pyrimidine-2,4-diamine-   4-6: 6-ethyl-N,N′-bis(3-hydroxyphenyl)-1,3,5-triazine-2,4-diamine-   4-11: N,N′-bis(3-hydroxyphenyl)-6-propyl-1,3,5-triazine-2,4-diamine-   4-26:    6-isobutyl-N,N′-bis(3-hydroxyphenyl)-1,3,5-triazine-2,4-diamine-   4-31: 6-s-butyl-N,N′-bis(3-hydroxyphenyl)-1,3,5-triazine-2,4-diamine-   4-36: 6-t-butyl-N,N′-bis(3-hydroxyphenyl)-1,3,5-triazine-2,4-diamine-   4-212:    6-ethyl-N,N′-bis(3-hydroxy-4-methylphenyl)-1,3,5-triazine-2,4-diamine    and-   5-1: N,N′-bis(3-hydroxyphenyl)pyridazine-3,6-diamine,    and most preferably-   2-methyl-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine and-   N,N′-bis(3-hydroxyphenyl)pyridazine-3,6-diamine.

MODE OF PRACTICING THE INVENTION

The nitrogen-containing heteroaryl compounds represented by generalformulae (I) of the present invention and the nitrogen-containingheteroaryl derivatives represented by general formulae (VII) and (VIII)are either known compounds (for example WO00/12485 pamphlet) or they canbe produced by the following method using known compounds as thestarting materials.

In the above formulae, R¹, R², Z¹, Z², Z³, Z⁴, Z⁵ and A have the samemeanings as above, and X¹ and X² each represents a halogen atom(preferably a chlorine atom, bromine atom or iodine atom, and morepreferably a chlorine atom).

Stage A-1 is a stage for the production of a compound of general formula(XI) by the reaction between a halogen compound of general formula (IX)and an aminophenol of general formula (X) in an inert solvent.

The inert solvent used is not particularly restricted providing it doesnot impede the reaction, and to some extent dissolves the startingmaterials. Examples include aliphatic hydrocarbons such as hexane,heptane, ligroin and petroleum ether; aromatic hydrocarbons such asbenzene, toluene and xylene; halo-hydrocarbons such as dichloromethane,chloroform, carbon tetrachloride, dichloroethane, chlorobenzene anddichlorobenzene; nitriles such as acetonitrile and propionitrile; etherssuch as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane and diethylene glycol dimethyl ether; amides such asformamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidoneand hexamethylphosphoramide; sulphoxides such as dimethylsulphoxide andsulfolane; and alcohols such as methanol, ethanol, propanol,2-ethoxyethanol and 2-butoxyethanol. The ethers, amides and alcohols arepreferred, in particular dioxane, diethylene glycol dimethyl ether,dimethylformamide, dimethylacetamide, 2-ethoxyethanol or2-butoxyethanol.

This stage can be carried out with the optional addition of a base, suchas an organic base like triethylamine, N-methylmorpholine, pyridine,4-(N,N-dimethylamino)-pyridine, or an alkali metal carbonate such assodium carbonate or potassium carbonate. An organic base is preferred.

The reaction temperature will differ with the starting materialcompounds and the solvent but, normally, it is 0-200° C. and preferably50-170° C.

The reaction time will vary with the reaction temperature, the startingmaterial compounds and the solvent but, normally, it is in the rangefrom 10 minutes to 24 hours, and preferably 30 minutes to 8 hours.

Following the end of the reaction, the target material can be obtainedfrom the reaction mixture by the usual methods. For example, followingthe end of the reaction the solvent is distilled off and water pouredonto the residue obtained, then extraction performed with awater-immiscible solvent (such as benzene, ether, ethyl acetate or thelike), after which the extraction liquid is washed with water and driedwith anhydrous magnesium sulphate. By then distilling off the solvent,the target compound is obtained. The target compound thus obtained can,where necessary, be further purified by the usual methods, such ascolumn chromatography, etc.

The aminophenol (X) used in stage A-1 is either a known compound or canbe readily produced by known methods [see J. Am. Chem. Soc., Vol. 47,1712-1718 (1925), J. Heterocyclic Chem., Vol. 26, 1255-1259 (1989),Synthesis, 1446-1450 (1997), J. Chem. Soc., 3017-3020 (1949), J. Chem.Soc., 2426-2430 (1951)].

Stage A-2 is a stage for the production of the target compound (I), andthis is achieved by performing reaction between the compound of generalformula (XI) and an amine of general formula (XII) in the same way as instage A-1.

In the case where compound (X) and compound (XII) are the same compound,then it is possible to obtain the desired compound (I) by carrying outreaction in the same way as in stage A-1 using at least 2 mol(preferably 2-3 mol) of compound (X) per mol of halo-compound (IX).

The amine of general formula (XII) used in stage A-2 is either a knowncompound or is readily produced by known methods [Synth. Commun., Vol.30, 3639-3644 (2000)].

The compound (IXa) where, in the compound of general formula (IX)employed in stage A-1, A is a group of formula (V) and R⁹ is a C₁₋₆alkyl group, can be produced by the following method B.

In the above formulae, X¹ and X² have the same meanings as above, and X³represents a halogen atom (preferably a chlorine atom, bromine atom oriodine atom, and more preferably a chlorine atom), and R¹² is a C₁₋₆alkyl group.

Stage B-1 is a stage based on a known method [Helv. Chim. Acta, Vol. 33,1365-1369 (1950)] and is carried out by the reaction between atrihalo-triazine compound of general formula (XIII) and an alkaliorgano-metal (for example, an organo-lithium reagent such asmethyllithium, ethyllithium or propyllithium; an organo-magnesiumreagent such as methylmagnesium bromide or ethyl-magnesium bromide; anorgano-aluminium reagent such as trimethylaluminum; an organo-zincreagent such as dimethylzinc; or an organo-copper reagent such aslithium dimethyl-cuprate; preferably an organo-lithium reagent or anorgano-magnesium reagent) in an inert solvent (for example an aliphatichydrocarbon such as hexane; an aromatic hydrocarbon such as benzene ortoluene; a halo-hydrocarbon such as dichloromethane; or an ether such asdiethyl ether or diethylene glycol dimethyl ether; preferably anaromatic hydrocarbon or an ether, and in particular benzene, toluene,tetrahydrofuran or diethyl ether), at −78° C. to 50° C. (preferably −30°C. to 30° C.) for from 10 minutes to 8 hours (preferably 30 minutes to 3hours).

After the completion of the reaction, the target compound is obtainedfrom the reaction mixture by the usual methods. For example, thereaction mixture is concentrated or extracted with a water-immiscibleorganic solvent (such as benzene, ether, ethyl acetate or the like),followed by drying with anhydrous magnesium sulphate, after which thesolvent is distilled off. Where required, the target material thusobtained can be further purified by normal methods, for example bycolumn chromatography.

The compound of general formula (IX) used in stage A-1 can also beproduced by the following method C.

In the above formulae, X¹, X² and A have the same meanings as above.

Stage C-1 is a stage based on a known method [J. Org. Chem., Vol. 17,1320-1327 (1952); J. Org. Chem., Vol. 18, 653-656 (1953); J. Am. Chem.Soc. Vol. 79, 2230-2232 (1957)] by the reaction between a compound ofgeneral formula (XIV) and a halogenating agent (such as a thionyl halidesuch as thionyl chloride; a phosphorus trihalide such as phosphorustrichloride, phosphorus tribromide or phosphorus triiodide; a phosphoruspentahalide such as phosphorus pentachloride, phosphorus pentabromide orphosphorus pentaiodide; or a phosphorus oxyhalide such as phosphorusoxychloride, phosphorus oxybromide or phosphorus oxyiodide; inparticular with phosphorus oxychloride) either in the absence of solventor in the presence of an inert solvent (such as an aliphatic hydrocarbonsuch as hexane or heptane; an aromatic hydrocarbon such as benzene ortoluene; a halo-hydrocarbon such as dichloroethane or dichlorobenzene;an ether such as diethyl ether or diethylene glycol dimethyl ether; oran organic base such as N-methylmorpholine, triethylamine,N-methyl-piperidine, pyridine, quinoline or dimethylaniline; preferablyin an organic base or in the absence of solvent, and in particular indimethylaniline), at 20-180° C. (preferably 70-150° C.) for from 1 hourto 24 hours (preferably 3 to 5 hours). In the case where no solvent isemployed, the reaction is carried out using excess of the halogenatingagent.

Following the end of the reaction, the target compound is obtained fromthe reaction mixture by the usual methods. For example, the reactionmixture is concentrated or extracted with a water-immiscible organicsolvent (such as benzene, ether, ethyl acetate or the like), followed bydrying with anhydrous magnesium sulphate, after which the solvent isdistilled off and the target material obtained. Where required, thetarget material thus obtained can be further purified by normal methods,for example by column chromatography.

In the case where the nitrogen-containing heteroaryl compounds ofgeneral formula (I) of the present invention, or pharmacologicallypermitted salts thereof, are used as preventives or remedies forAlzheimer's disease or as amyloid protein fibril-formation inhibitors,they can be administered orally in the form of tablets, capsules,granules, powders or syrups, etc, or parenterally in the form ofinjections or suppositories, etc, either on their own or after mixingwith suitable pharmacologically-permitted fillers, diluents or the like.

These pharmaceutical preparations are produced by known methods usingadditives such as fillers/excipients (examples of which are organicfillers like lactose, sucrose, glucose, mannitol, sorbitol or othersugar or sugar derivative; corn starch, potato starch, α-starch, dextrinor other such starch or starch derivative; crystalline cellulose orother such cellulose derivative; gum Arabic; dextran; pullulan or thelike; and inorganic fillers like light silica, synthetic aluminiumsilicate, calcium silicate, magnesium metasilicate or other silicic acidderivative; calcium hydrogen phosphate or other phosphate; calciumcarbonate or other carbonate; calcium sulphate or other sulphate, or thelike), lubricants (examples of which are stearic acid and metalstearates like calcium stearate and magnesium stearate; talc; colloidalsilica; beeswax, sperm whale wax and other such waxes; boric acid;adipic acid; sulphates such as sodium sulphate; glycol; fumaric acid;sodium benzoate; DL-leucine; sodium laurylsulphate, magnesiumlaurylsulphate and other such laurylsulphates; silicic anhydride,silicic acid hydrate and other silicas; and also the aforesaid starchderivatives), binders (examples of which are hydroxypropyl cellulose,hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, macrogol andcompounds identical to the aforesaid fillers), disintegrating agents(cellulose derivatives such as hydroxypropyl cellulose with a low degreeof substitution, carboxymethyl cellulose, calcium carboxymethylcellulose and internally-crosslinked sodium carboxymethyl cellulose;carboxymethyl starch, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone and other such chemically-modified starch/cellulose or thelike), emulsifiers (for example bentonite, veegum and other types ofcolloidal clay; magnesium hydroxide, aluminium hydroxide and other suchmetal hydroxides; sodium lauryl sulphate, calcium stearate and othersuch anionic surfactants; benzalkonium chloride and other types ofcationic surfactants; and polyoxyethylene alkyl ether, polyoxyethylenesorbitan fatty acid ester, sucrose fatty acid ester and other suchnonionic surfactants), stabilizers (methyl paraben, propyl paraben andother such p-hydroxybenzoic acid esters; chlorobutanol, benzyl alcohol,phenyl ethyl alcohol and other such alcohols; benzalkonium chloride;phenol, cresol and other such phenols; thimerosal; dehydroacetic acid;and sorbic acid), correctives/corrigents (such as the normally usedsweeteners, acidic taste-conferrers, spices and the like), diluents andother such additives.

The amount used will differ according to the symptoms, age, etc, butwhen administered orally to an adult there can be used an amount betweena lower limit of 1 mg (preferably 10 mg) and an upper limit of 1,000 mg(preferably 500 mg) per time, and when administered intravenously therecan be used an amount between a lower limit of 0.5 mg (preferably 5 mg)and an upper limit of 500 mg (preferably 250 mg) per time, from once tosix times per day according to the symptoms.

OPTIMUM MODE FOR PRACTICING THE INVENTION

Below, the present invention is explained in still further detail byproviding some production examples, experimental and preparationexamples, but the invention is not to be restricted to these.

Production Example 16-Ethyl-N,N′-bis(3-hydroxyphenyl)-1,3,5-triazine-2,4-diamine(Exemplified Compound No. 4-6)

(1A) 2,4-dichloro-6-ethyl-1,3,5-triazine

This compound was prepared based on a known method [Helv. Chem. Acta,33, 1365-1369 (1950)]. That is to say, 2,4,6-trichloro-1,3,5-triazine(4.61 g, 25.0 mmol) was dissolved in benzene (50.0 mL) under anatmosphere of nitrogen and the solution cooled with an ice bath.

While stirring the solution, ethylmagnesium bromide (3.0 M ethersolution, 10.0 mL) was slowly added over 20 minutes and stirring carriedout for a further 30 minutes while ice cooling. The reaction wasmonitored by thin layer chromatography and, following the end of thereaction, saturated aqueous ammonium chloride solution (20.0 mL) wasadded to the reaction liquid and stirring carried out. Ether (200 mL)was also added and liquid separation performed. The organic layerobtained was removed, washed with distilled water (20.0 mL) and thenwith saturated sodium chloride solution (20.0 mL), after which dryingwas carried out with anhydrous magnesium sulphate. By distilling off thesolvent under reduced pressure, the crude target compound was obtained.

The crude compound thus obtained was purified using silica gelchromatography (elution solvent: hexane/ethyl acetate=100/1, v/v) andthe target compound obtained (2.67 g, 60% yield).

(1B) 6-ethyl-N,N′-bis(3-hydroxyphenyl)-1,3,5-triazine-2,4-diamine

After dissolving 3-aminophenol (2.18 g, 20 mmol) in 1,4-dioxane (20.0mL), 2,4-dichloro-6-ethyl-1,3,5-triazine (1.78 g, 10 mmol) was added andstirring carried out for 3 hours at 100° C. under a nitrogen atmosphere.

Following the end of the reaction, the solvent was distilled off underreduced pressure and the residue purified using silica gel columnchromatography (elution solvent: methylene chloride/methanol=20/1, v/v)and the target compound obtained (2.26 g, yield 70%).

¹H NMR spectrum (DMSO, 400 MHz), δ: 1.29 (3H, t, J=7.6 Hz), 2.68 (2H, q,J=7.6 Hz), 6.59 (2H, d, J=7.2 Hz), 7.04 (2H, brs), 7.13 (2H, t, J=8.0Hz), 7.18 (2H, d, J=7.2 Hz).

Mass spectrum (EI), m/z: 323 (M⁺)

Production Example 22-Ethyl-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine (ExemplifiedCompound No. 1-3)

(2A) 4,6-dichloro-2-ethylpyrimidine

Preparation was carried out based on a known method [J. Org., Vol. 18,653-656 (1953)]. That is to say, an excess amount of phosphoryl chloride(6.34 mL, 70.0 mmol) was added to 2-ethyl-1H-pyrimidine-4,6-dione (1.40g, 10.0 mmol) and the reaction mixture heated under reflux for 2 hours.After the solid material had completely dissolved, the reaction mixturewas cooled to room temperature, and the unreacted phosphoryl chloridedistilled off under reduced pressure. The residue was added to finelycrushed ice (200 g) and left. After the ice had melted, ether (200 mL)was added to the reaction mixture, and liquid separation performed. Theorganic layer obtained was removed, washed with distilled water (20.0mL) and then with saturated aqueous sodium chloride solution (20.0 mL),after which drying was performed with anhydrous magnesium sulphate. Bydistilling off the solvent under reduced pressure, crude target compoundwas obtained (1.68 g, crude yield 95%).

The crude compound obtained was used in the next reaction withoutfurther purification.

(2B) 2-ethyl-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine

After dissolving 3-aminophenol (1.09 g, 10.0 mmol) in 2-ethoxyethanol(5.0 mL), 4,6-dichloro-2-ethylpyrimidine (0.89 g, 5.0 mmol) was addedand stirring carried out for 5 hours at 130° C.

The reaction was monitored by thin layer chromatography and, followingthe end of the reaction, the solvent was distilled off under reducedpressure. The residue was purified using silica gel columnchromatography (elution solvent: methylene chloride/methanol=20/1, v/v)and the target compound obtained (0.97 g, yield 60%).

¹H NMR spectrum (DMSO, 400 MHz), δ: 1.27 (3H, t, J=7.4 Hz), 2.62 (2H, q,J=7.4 Hz), 6.06 (1H, s), 6.37 (2H, m), 6.96 (2H, m), 7.01-7.09 (4H, m),8.91 (2H, brs), 9.27 (2H, m).

Mass spectrum (EI), m/z: 322 (M⁺)

Production Example 32-Methyl-N-(3-hydroxyphenyl)-N′-(3-methoxyphenyl)-pyrimidine-4,6-diamine(Exemplified Compound No. 1-108)

(3A) 2-methyl-4-chloro-6-(3-hydroxyphenylamino)-pyrimidine

4,6-dichloro-2-methylpyrimidine (1.63 g, 10.0 mmol) prepared based onthe method described in Production Example 2A above using2-methyl-1H-pyrimidine-4,6-dione instead of the2-ethyl-1H-pyrimidine-4,6-dione, was slowly added to a 2-ethoxyethanol(5.0 mL) solution of 3-aminophenol (1.09 g, 10.0 mmol) and the reactionmixture heated for 4 hours at 130° C. The reaction was monitored by thinlayer chromatography and, following the end of the reaction, thereaction mixture was cooled to room temperature and the precipitatedwhite powder filtered off. The crude product filtered off was used inthe subsequent reaction without further purification (1.76 g, crudeyield 75%).

¹H NMR spectrum (DMSO, 400 MHz), δ: 2.42 (3H, s), 6.50 (1H, m), 6.73(1H, s), 7.05 (1H, m), 7.12 (1H, m), 7.19 (1H, s), 10.00 (1H, s).

Mass spectrum (EI), m/z: 234 (M−H⁺)

(3B)2-methyl-N-(3-hydroxyphenyl)-N′-(3-methoxyphenyl)-pyrimidine-4,6-diamine

2-methyl-4-chloro-6-(3-hydroxyphenylamino)pyrimidine (0.71 g, 3.0 mmol)was added to a 2-ethoxyethanol (2.0 mL) solution of 3-methoxyaniline(0.37 g, 3.0 mmol) under a nitrogen atmosphere and the reaction mixturestirred for 5 hours at 130° C.

The reaction was monitored by thin layer chromatography and, at the endof the reaction, the solvent was distilled off under reduced pressure.The residue was purified using silica gel column chromatography (elutionsolvent: methylene chloride/methanol=20/1, v/v) and the target compoundobtained (0.48 g, yield 50%)

¹H NMR spectrum (CDCl₃, 400 MHz), δ: 2.40 (3H, s), 3.75 (3H, s), 6.16(1H, s), 6.59-6.74 (4H, m), 6.75 (1H, t, J=2.2 Hz), 6.83 (1H, t, J=2.2Hz), 6.95 (2H, brs), 7.13 (1H, t, J=8.0 Hz), 7.18 (1H, t, J=8.0 Hz).

Mass spectrum (EI), m/z: 322 (M⁺)

Production Example 42-Methyl-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine (ExemplifiedCompound No. 1-2)

This compound was obtained (yield 60%) based on the method described inProduction Example 2B using 4,6-dichloro-2-methylpyrimidine instead ofthe 4,6-dichloro-2-ethylpyrimidine.

¹H NMR spectrum (DMSO, 400 MHz), δ: 2.35 (3H, s), 6.05 (1H, s), 6.35(2H, m), 6.92 (2H, m), 7.00-7.10 (4H, m), 8.95 (1H, brs), 9.30 (1H, s).

Mass spectrum (EI), m/z: 308 (M⁺)

Production Example 5 N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine(Exemplified Compound No. 1-1)

This compound was obtained (yield 60%) based on the method described inProduction Example 2B using 4,6-dichloropyrimidine instead of the4,6-dichloro-2-ethylpyrimidine.

¹H NMR spectrum (DMSO, 400 MHz), δ: 6.20 (1H, s), 6.38 (2H, m), 6.92(2H, m), 7.01-7.13 (4H, m), 8.25 (1H, s), 9.02 (1H, s), 9.31 (1H, s).

Mass spectrum (EI), m/z: 294 (M⁺)

Production Example 6 N,N′-bis(3-hydroxyphenyl)pyrimidine-2,4-diamine(Exemplified Compound No. 2-1)

This compound was obtained (yield 80%) based on the method described inProduction Example 2B using 2,4-dichloropyrimidine instead of the4,6-dichloro-2-ethylpyrimidine.

¹H NMR spectrum (DMSO, 400 MHz), δ: 6.46 (2H, d, J=8.6 Hz), 6.63 (2H,m), 6.85 (1H, s), 6.95-7.06 (2H, m), 7.10-7.30 (3H, m), 7.93 (1H, d,J=8.2 Hz), 9.62 (1H, brs), 10.47 (1H, s), 10.80 (1H, s).

Mass spectrum (EI), m/z: 294 (M⁺)

Production Example 75,6-Dimethyl-N,N′-bis(3-hydroxyphenyl)pyrimidine-2,4-diamine(Exemplified Compound No. 2-11)

This compound was obtained (yield 78%) based on the method described inProduction Example 2B using 2,4-dichloro-5,6-dimethylpyrimidine insteadof the 4,6-dichloro-2-ethylpyrimidine.

¹H NMR spectrum (DMSO, 400 MHz), δ: 2.12 (3H, s), 2.37 (3H, s), 6.49(1H, dd, J=1.6, 8.2 Hz), 6.67 (2H, m), 6.88 (1H, t, J=1.6 Hz), 6.94-7.20(2H, m), 7.06 (1H, d, J=8.2 Hz), 7.18 (1H, t, J=8.2 Hz), 9.40-9.60 (4H,brs).

Mass spectrum (EI), m/z: 322 (M⁺)

Production Example 82-Butyl-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine (ExemplifiedCompound No. 1-6)

This compound was obtained (yield 73%) based on the method described inProduction Example 2B using 4,6-dichloro-2-butylpyrimidine instead ofthe 4,6-dichloro-2-ethylpyrimidine.

¹H NMR spectrum (DMSO, 400 MHz), δ: 0.94 (3H, t, J=7.5 Hz), 1.38 (2H,sextet, J=7.5 Hz), 1.76 (2H, quintet, J=7.5 Hz), 2.64 (2H, t, J=7.5 Hz),6.08 (1H, s), 6.44 (1H, dd, J=1.6, 8.0 Hz), 6.95 (2H, d, J=8.0 Hz), 7.00(2H, m), 7.08 (2H, t, J=8.0 Hz), 9.17 (2H, s), 9.40 (2H, s).

Mass spectrum (EI), m/z: 350 (M⁺)

Production Example 92-Propyl-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine (ExemplifiedCompound 1-4)

This compound was obtained (yield 68%) based on the method described inProduction Example 2B using 4,6-dichloro-2-propylpyrimidine instead ofthe 4,6-dichloro-2-ethylpyrimidine.

¹H NMR spectrum (DMSO, 400 MHz), δ: 0.96 (3H, t, J=7.2 Hz), 1.79 (2H,sextet, J=7.2 Hz), 2.58 (2H, t, J=7.2 Hz), 6.06 (1H, s), 6.37 (2H, dd,J=1.2, 7.6 Hz), 6.96 (2H, d, J=8.8 Hz), 7.02-7.07 (4H, m), 8.90 (2H, s),9.28 (22H, s).

Mass spectrum (EI), m/z: 336 (M⁺)

Production Example 10N,N′-bis(3-hydroxyphenyl)-6-propyl-1,3,5-triazine-2,4-diamine(Exemplified Compound 4-11)

This compound was obtained (yield 62%) based on the method described inProduction Example 1B using 2,4-dichloro-6-propyl-1,3,5-triazine insteadof the 2,4-dichloro-6-ethyl-1,3,5-triazine.

¹H NMR spectrum (DMSO, 400 MHz), δ: 0.96 (3H, t, J=7.2 Hz), 1.77 (2H,sextet, J=7.2 Hz), 2.51 (2H, t, J=7.2 Hz), 6.42 (2H, dd, J=2.0, 8.0 Hz),7.05 (2H, t, J=8.0 Hz), 7.14 (2H, brs), 7.31 (2H, d, J=8.0 Hz), 9.26(2H, brs), 9.51 (2H, brs).

Mass spectrum (EI), m/z: 337 (M⁺)

Production Example 11N-ethyl-N,N′-bis(3-hydroxyphenyl)-2-methylpyrimidine-4,6-diamine(Exemplified Compound No. 1-30)

This compound was obtained (yield 45%) based on the method described inProduction Example 3B using 3-ethylaminophenol instead of the3-methoxyaniline.

¹H NMR spectrum (DMSO, 400 MHz), δ: 1.06 (3H, t, J=7.3 Hz), 2.32 (3H,s), 3.87 (2H, q, J=7.3 Hz), 5.39 (1H, s), 6.25 (1H, dd, J=2.2, 8.0 Hz),6.61 (1H, m), 6.66 (1H, d, J=8.0 Hz), 6.71 (1H, dd, J=2.2, 8.0 Hz), 6.86(1H, d, 3=8.0 Hz), 6.92 (1H, t, J=8.0 Hz), 7.05 (1H, m), 7.25 (1H, t,J=8.0 Hz), 8.28 (1H, s), 8.68 (1H, s), 9.17 (1H, brs), 9.65 (2H, brs).

Mass spectrum (EI), m/z: 336 (M⁺)

Production Example 12 N,N′-bis(3-hydroxyphenyl)pyridazine-3,6-diamineExemplified Compound 5-1

This compound was obtained (yield 55%) based on the method described inProduction Example 2B using 3,6-dichloropyridazine instead of the4,6-dichloro-2-ethylpyrimidine.

¹H NMR spectrum (DMSO, 400 MHz), δ: 6.28 (2H, dd, J=2.2, 7.7 Hz),6.96-7.07 (4H, m), 7.06 (2H, s), 7.44 (2H, t, J=2.2 Hz), 8.78 (1H, s),9.23 (1H, s).

Mass spectrum (EI), m/z: 294 (M⁺)

Production Example 132-Amino-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine (ExemplifiedCompound No. 1-22)

This compound was obtained (yield 55%) based on the method described inProduction Example 2B using 2-amino-4,6-dichloropyrimidine instead ofthe 4,6-dichloro-2-ethylpyrimidine.

¹H NMR spectrum (DMSO, 400 MHz), δ: 5.49 (1H, s), 6.35 (2H, d, J=8.0Hz), 6.75 (2H, brs), 6.77-6.86 (4H, m), 6.96 (2H, t, J=8.0 Hz), 9.14(2H, brs), 9.36 (2H, brs).

Mass spectrum (FAB), m/z: 310 (M+H⁺)

Production Example 142-Methylthio-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine(Exemplified Compound No. 1-20)

This compound was obtained (yield 62%) based on the method described inProduction Example 2B using 4,6-dichloro-2-methylthio-pyrimidine insteadof the 4,6-dichloro-2-ethylpyrimidine.

¹H NMR spectrum (DMSO, 400 MHz), δ: 2.48 (3H, s), 5.91 (1H, s), 6.39(2H, dd, J=1.4, 8.0 Hz), 6.92 (2H, d, J=8.0 Hz), 6.99 (2H, m), 7.06 (2H,t, J=8.0 Hz), 9.01 (2H, s), 9.31 (2H, s),

Mass spectrum (EI), m/z: 340 (M⁺)

Production Example 152-Methylthio-N,N′-diethyl-N,N′-bis(3-hydroxyphenyl)-pyrimidine-4,6-diamine(Exemplified Compound No. 1-71)

This compound was obtained (yield 43%) based on the method described inProduction Example 2B using 4,6-dichloro-2-methylthio-pyrimidine insteadof the 4,6-dichloro-2-ethylpyrimidine, and using 3-ethylaminophenolinstead of the 3-aminophenol.

¹H NMR spectrum (DMSO, 400 MHz), δ: 1.04 (6H, t, J=7.3 Hz), 2.42 (3H,s), 3.80 (4H, q, =7.3 Hz), 4.87 (1H, s), 6.50-6.60 (6H, m), 7.09 (2H, t,J=8.0 Hz), 9.42 (2H, brs).

Mass spectrum (EI), m/z: 396 (M⁺)

Production Example 166-Butoxy-N,N′-bis(3-hydroxyphenyl)-1,3,5-triazine-2,4-diamine(Exemplified Compound No. 4-81)

This compound was obtained (yield 62%) based on the method described inProduction Example 1B using 6-butoxy-2,4-dichloro-1,3,5-triazine (10.0mmol) instead of the 2,4-dichloro-6-ethyl-1,3,5-triazine.

¹H NMR spectrum (DMSO, 400 MHz), δ: 0.94 (3H, t, J=7.2 Hz), 1.42 (2H,sextet, J=7.2 Hz), 1.70 (2H, quintet, J=7.2 Hz), 4.31 (2H, t, J=7.2 Hz),6.43 (2H, dd, J=2.0, 8.0 Hz), 7.05 (2H, t, J=8.0 Hz), 7.14 (2H, brs),7.25 (2H, brs), 9.28 (2H, brs), 9.45 (2H, brs).

Mass spectrum (FAB), m/z: 368 (M+H⁺)

Production Example 176-Butoxy-N,N′-diethyl-N,N′-bis(3-hydroxyphenyl)-1,3,5-triazine-2,4-diamine(Exemplified Compound No. 4-85)

This compound was obtained (yield 47%) based on the method described inProduction Example 1B using 6-butoxy-2,4-dichloro-1,3,5-triazine insteadof the 2,4-dichloro-6-ethyl-1,3,5-triazine, and using 3-ethylaminophenolinstead of the 3-aminophenol.

¹H NMR spectrum (DMSO, 400 MHz), δ: 0.83 (3H, t, J=7.3 Hz), 1.08 (6H,m), 1.24 (2H, m), 1.52 (2H, m), 3.79 (4H, m), 4.02 (2H, m), 6.60-6.70(6H, m), 7.15 (2H, t, J=8.0 Hz).

Mass spectrum (FAB), m/z: 424 (M+H⁺)

Production Example 18N,N′-bis(3-hydroxyphenyl)-5-nitropyrimidine-4,6-diamine (ExemplifiedCompound No. 1-173)

This compound was obtained (yield 80%) based on the method described inProduction Example 2B using 4,6-dichloro-5-nitropyrimidine instead ofthe 4,6-dichloro-2-ethylpyrimidine.

¹H NMR spectrum (DMSO, 400 MHz), δ: 6.65 (2H, m), 7.95 (2H, m),7.10-7.22 (4H, m), 8.20 (1H, s), 9.60 (2H, m), 10.80 (2H, brs).

Mass spectrum (EI), m/z: 339 (M⁺)

Production Example 19N,N′-bis(3-hydroxy-2-methylphenyl)pyrimidine-4,6-diamine (ExemplifiedCompound No. 1-86)

This compound was obtained (yield 40%) based on the method described inProduction Example 2B using 4,6-dichloropyrimidine instead of the4,6-dichloro-2-ethylpyrimidine, and using 3-amino-2-methylphenol insteadof the 3-aminophenol.

¹H NMR spectrum (DMSO, 400 MHz), δ: 1.95 (6H, s), 5.48 (1H, s), 6.61(2H, d, J=5.3 Hz), 6.73 (2H, d, J=5.3 Hz), 6.92 (2H, d, J=5.3 Hz), 8.00(1H, s), 8.29 (1H, s), 9.30 (1H, brs).

Mass spectrum (EI), m/z: 322 (M⁺)

Production Example 20N,N′-(3-hydroxy-2-methylphenyl)pyrimidine-2,4-diamine (ExemplifiedCompound No. 2-101)

This compound was obtained (yield 50%) based on the method described inProduction Example 2B using 2,4-dichloropyrimidine (0.74 g, 5.00 mmol)instead of the 4,6-dichloro-2-ethylpyrimidine, and using3-amino-2-methylphenol instead of the 3-aminophenol.

Mass spectrum (EI), m/z: 322 (M⁺)

Production Example 21N,N′-bis(3-hydroxy-4-methoxyphenyl)pyrimidine-4,6-diamine (ExemplifiedCompound No. 1-88)

This compound was obtained (yield 67%) based on the method described inProduction Example 2B using 4,6-dichloropyrimidine instead of the4,6-dichloro-2-ethylpyrimidine, and using 3-amino-4-methoxyphenolinstead of the 3-aminophenol.

¹H NMR spectrum (DMSO, 400 MHz), δ: 3.73 (6H, s), 5.93 (1H, s), 6.81(4H, m), 7.00 (2H, s), 8.12 (1H, s), 8.71 (1H, brs), 8.99 (1H, brs).

Mass spectrum (EI), m/z: 354 (M⁺)

Production Example 226-Methyl-N,N′-bis(3-hydroxyphenyl)pyrimidine-2,4-diamine (ExemplifiedCompound 2-6)

This compound was obtained (yield 71%) based on the method described inProduction Example 2B using 2,4-dichloro-6-methylpyrimidine instead ofthe 4,6-dichloro-2-ethylpyrimidine.

¹H NMR spectrum (DMSO, 400 MHz), δ: 2.36 (3H, s), 6.17 (1H, s), 6.46(1H, dd, J=1.9, 8.5 Hz), 6.50 (1H, dd, J=1.9, 8.5 Hz), 6.94 (1H, s),7.01-7.12 (3H, m), 7.20 (2H, t, J=8.5 Hz), 9.35 (1H, s), 9.44 (1H, s),9.50 (1H, brs), 9.80 (1H, brs).

Mass spectrum (EI), m/z: 308 (M⁺)

Production Example 232-Methyl-N-(3-chlorophenyl)-N′-(3-hydroxyphenyl)-pyrimidine-4,6-diamine(Exemplified Compound 1-161)

This compound was obtained (yield 57%) based on the method described inProduction Example 3B using 3-chloroaniline instead of the3-methoxyaniline.

¹H NMR spectrum (CDCl₃, 400 MHz), δ: 3.49 (3H, s), 6.10 (1H, s), 6.62(1H, dd, J=2.0, 7.6 Hz), 6.73-6.78 (3H, m), 7.04-7.11 (2H, m), 7.17-7.25(2H, m), 7.33 (1H, t, J=2.0 Hz).

Mass spectrum (EI), m/z: 326 (M⁺)

Production Example 242-Methyl-N,N′-bis(4,6-difluoro-3-hydroxyphenyl)-pyrimidine-4,6-diamine(Exemplified Compound No. 1-171)

This compound was obtained (yield 57%) based on the method described inProduction Example 2B using 4,6-dichloro-2-methylpyrimidine instead ofthe 4,6-dichloro-2-ethylpyrimidine, and using 5-amino-2,4-difluorophenolinstead of the 3-aminophenol.

¹H NMR spectrum (DMSO, 400 MHz), δ 2.30 (3H, s), 5.77 (1H, s), 7.21 (2H,t, ³J_(HF)=11.0 Hz), 7.41 (2H, t, ⁴J_(HF)=8.8 Hz), 8.58 (2H, brs), 9.79(2H, brs).

Mass spectrum (EI), m/z: 380 (M⁺)

Production Example 252-Isopropyl-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine (ExemplifiedCompound No. 1-5)

This compound was obtained (yield 65%) based on the method described inProduction Example 2B using 4,6-dichloro-2-isopropylpyrimidine insteadof the 4,6-dichloro-2-ethylpyrimidine.

¹H NMR spectrum (CD₃OD, 400 MHz), δ: 1.32 (6H, d, J=6.9 Hz), 2.88 (1H,septet, J=6.9 Hz), 6.08 (1H, s), 6.47 (2H, ddd, J=0.9, 2.2, 8.1 Hz),6.90 (2H, ddd, J=0.9, 2.2, 8.1 Hz), 6.98 (2H, t, J=2.2 Hz), 7.09 (2H, t,J=8.1 Hz).

Mass spectrum (EI), m/z: 336 (M⁺)

Production Example 262-Methyl-N,N′-bis(3-hydroxy-5-trifluoromethylphenyl)-pyrimidine-4,6-diamine(Exemplified Compound No. 1-90)

This compound was obtained (yield 43%) based on the method described inProduction Example 2B using 4,6-dichloro-2-methylpyrimidine instead ofthe 4,6-dichloro-2-ethylpyrimidine, and using3-amino-5-trifluoromethyl-phenol instead of the 3-aminophenol.

¹H NMR spectrum (CD₃OD, 400 MHz), δ: 2.46 (3H, s), 6.05 (1H, s), 6.68(2H, m), 7.30 (2H, m), 7.34 (2H, t, J=2.0 Hz).

Mass spectrum (EI), m/z: 444 (M⁺)

Production Example 27N,N′-bis(3-hydroxyphenyl)-6-methyl-1,3,5-triazine-2,4-diamine(Exemplified Compound No. 4-1)

This compound was obtained (yield 73%) based on the method described inProduction Example 1B using 2,4-dichloro-6-methyl-1,3,5-triazine insteadof the 2,4-dichloro-6-ethyl-1,3,5-triazine.

¹H NMR spectrum (DMSO, 400 MHz), δ: 2.29 (3H, s), 6.43 (2H, dd, J=2.4,8.0 Hz), 7.06 (2H, t, J=8.0 Hz), 7.13 (2H, brs), 7.30 (2H, d, J=8.0 Hz),9.27 (2H, brs), 9.53 (2H, brs).

Mass spectrum (EI), m/z: 309 (M⁺)

Production Example 286-Butyl-N,N′-bis(3-hydroxyphenyl)-1,3,5-triazine-2,4-diamine(Exemplified Compound No. 4-21)

This compound was obtained (yield 68%) based on the method described inProduction Example 1B using 6-butyl-2,4-dichloro-1,3,5-triazine insteadof the 2,4-dichloro-6-ethyl-1,3,5-triazine.

¹H NMR spectrum (DMSO, 400 MHz), δ: 0.92 (3H, t, J=7.3 Hz), 1.37 (2H,sextet, J=7/3 Hz), 1.73 (2H, quintet, J=8.0 Hz), 2.51 (2H, m), 6.42 (2H,dd, J=2.5, 8.0 Hz), 7.05 (2H, t, J=8.0 Hz), 7.13 (2H, s), 7.31 (2H, d,J=8.0 Hz), 9.26 (2H, brs), 9.51 (2H, brs).

Mass spectrum (EI), m/z: 351 (M⁺)

Production Example 29N,N′-dimethyl-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine(Exemplified Compound No. 1-28)

This compound was obtained (yield 43%) based on the method described inProduction Example 2B using 4,6-dichloropyrimidine instead of the4,6-dichloro-2-ethylpyrimidine, and using 3-methylaminophenol instead ofthe 3-aminophenol.

¹H NMR spectrum (DMSO, 400 MHz), δ: 3.28 (6H, s), 5.50 (1H, s),6.54-6.64 (6H, m), 7.11 (2H, t, J=8.0 Hz), 8.21 (1H, s), 9.50 (2H, brs).

Mass spectrum (EI), m/z: 340 (M⁺)

Production Example 302-Methyl-N,N′-dimethyl-N,N′-bis(3-hydroxyphenyl)-pyrimidine-4,6-diamine(Exemplified Compound No. 1-31)

This compound was obtained (yield 45%) based on the method described inProduction Example 2B using 4,6-dichloro-2-methylpyrimidine instead ofthe 4,6-dichloro-2-ethylpyrimidine, and using 3-methylaminophenolinstead of the 3-aminophenol.

¹H NMR spectrum (DMSO, 400 MHz), δ: 2.31 (3H, s), 3.28 (6H, s), 5.35(1H, s), 6.53-6.61 (6H, m), 7.09 (2H, t, J=8.0 Hz), 9.48 (2H, brs).

Mass spectrum (EI), m/z: 336 (M⁺)

Production Example 316-Isobutyl-N,N′-bis(3-hydroxyphenyl)-1,3,5-triazine-2,4-diamine(Exemplified Compound No. 4-26)

This compound was obtained (yield 50%) based on the method described inProduction Example 1B using 6-isobutyl-2,4-dichloro-1,3,5-triazineinstead of the 2,4-dichloro-6-ethyl-1,3,5-triazine.

¹H NMR spectrum (DMSO, 400 MHz), δ: 0.99 (6H, d, J=6.8 Hz), 2.42 (1H,m), 2.49 (2H, d, J=7.2 Hz), 6.54 (2H, dd, J=1.5, 8.0 Hz), 7.00-7.09 (2H,m), 7.11 (2H, t, J=8.0 Hz), 7.21 (2H, m).

Mass spectrum (EI), m/z: 351 (M⁺)

Production Example 326-Ethyl-N,N′-bis(3-hydroxy-4-methylphenyl)-1,3,5-triazine-2,4-diamine(Exemplified Compound No. 4-212)

This compound was obtained (yield 55%) based on the method described inProduction Example 1B using 3-amino-3-methylphenol {sic} instead of the3-aminophenol.

¹H NMR spectrum (DMSO, 400 MHz), δ: 1.13 (3H, t, J=7.2 Hz), 1.96 (6H,s), 2.51 (2H, q, J=7.2 Hz), 6.87 (2H, d, J=8.0 Hz), 6.98 (2H, brs), 7.02(2H, d, J=8.0 Hz).

Mass spectrum (EI), m/z: 351 (M⁺)

Production Example 336-t-Butyl-N,N′-bis(3-hydroxyphenyl)-1,3,5-triazine-2,4-diamine(Exemplified Compound No. 4-36)

This compound was obtained (yield 48%) based on the method described inProduction Example 1B using 6-t-butyl-2,4-dichloro-1,3,5-triazineinstead of the 2,4-dichloro-6-ethyl-1,3,5-triazine.

¹H NMR spectrum (DMSO, 400 MHz), δ: 1.32 (9H, s), 6.43 (2H, dd, J=2.0,8.0 Hz), 7.06 (2H, t, J=8.0 Hz), 7.20 (2H, brs), 7.34 (2H, d, J=8.0 Hz),9.27 (2H, brs), 9.39 (2H, brs).

Mass spectrum (EI), m/z: 351 (M⁺)

Production Example 346-s-Butyl-N,N′-bis(3-hydroxyphenyl)-1,3,5-triazine-2,4-diamine(Exemplified Compound No. 4-31)

This compound was obtained (yield 52%) based on the method described inProduction Example 1B using 6-s-butyl-2,4-dichloro-1,3,5-triazineinstead of the 2,4-dichloro-6-ethyl-1,3,5-triazine.

¹H NMR spectrum (DMSO, 400 MHz), δ: 0.90 (3H, t, J=7.4 Hz), 1.26 (3H, d,J=6.4 Hz), 1.59 (1H, ddq, J=6.4, 7.4, 14.0 Hz), 1.83 (1H, ddq, J=6.4,7.4, 14.0 Hz), 2.60 (1H, ddq, J=6.4, 6.4, 6.4 Hz), 4.00 (2H, brs), 6.51(2H, d, J=7.2 Hz), 7.09 (2H, d, J=7.5 Hz), 7.12 (2H, s), 7.27 (2H, d,J=7.5 Hz), 9.40 (1H, brs), 9.90 (1H, brs).

Mass spectrum (EI), m/z: 351 (M⁺)

Example 1 Action in Inhibiting the Lowering of MTT Reduction Capacity

The HeLa cells employed were purchased from the Dainippon PharmaceuticalCo.

The HeLa cells were seeded by suspension in MEM (Minimum essentialmedium; produced by the Sigma Chemical Co.) containing 10% inactivatedFBS (foetal bovine serum) such that there were 1,000 per well in a96-well microplate, and then culturing was carried out overnight in anincubator at 37° C. in the presence of 5% CO₂.

The test compound was dissolved in dimethyl sulphoxide (DMSO) anddiluted with the MEM medium so that the final concentration of DMSO wasno more than 0.1 wt %, and added to the cells seeded the previous day. Asolution of β-amyloid protein (Aβ1-40: produced by the Sigma ChemicalCo.) dissolved in MEM medium was added so the final Aβ1-40 concentrationwas 100 ng/mL. Overnight culturing was carried out using an incubator at37° C. in the presence of 5% CO₂, with 100 μL/well of MEM mediumcontaining 5% deactivated FBS.

Now, prior to use, the Aβ1-40 had been dissolved in buffer and leftovernight so that the amyloid coagulated.

In order to determine the percentage inhibition of the test compound,cells alone, cells where Aβ1-40 had been added, and cells where only thetest compound had been added, were also incubated overnight under thesame conditions.

The following day, there was added 10 μL/well of MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide: producedby Wako Pure Chemical Industries] prepared at a concentration of 5 mg/mLwith phosphate buffered saline (PBS), and incubation carried out for 2hours at 37° C. in the presence of 5% CO₂. The medium was theneliminated and the formazan dye produced measured calorimetrically (A570nm-A650 nm) using a Microplate Reader (produced by the Molecular DevicesCo.), by dissolving with the addition of 100 μL per well of isopropanol.In this way, the change in the MTT reduction capacity of the HeLa cellswas measured.

The percentage inhibition (%) by the test compound was determined fromthe following formula.

inhibition (%) [(a−b)/(a−c)]×100

where

-   a=MTT reduction capacity when untreated-   b=MTT reduction capacity when Aβ1-40 and the test compound are added-   c=MTT reduction capacity when only Aβ1-40 is added

Table 6 shows the action in inhibiting the lowering of the MTT reductioncapacity by Aβ1-40 (100 nM) in HeLa cells, denoted by the 50% inhibitoryconcentration (IC50).

As can seen from Table 6, the compounds of the present invention showoutstanding action in inhibiting a lowering of the MTT reductioncapacity.

TABLE 6 Test Compound IC50 (μm) compound of Production Example 1 3.5compound of Production Example 2 1.9 compound of Production Example 46.0 compound of Production Example 5 9.6 compound of Production Example6 6.7 compound of Production Example 8 5.5 compound of ProductionExample 9 2.4 compound of Production Example 10 4.2 compound ofProduction Example 13 5.5 compound of Production Example 18 3.8 compoundof Production Example 27 2.4 compound of Production Example 33 2.2compound of Production Example 34 4.1 compound of Production Example 352.1 compound of Production Example 36 5.8

When testing was carried out by the same method as above using4-(7-hydroxy-2,4,4-trimethyl-chroman-4-yl)benzene-1,3-diol, and theaction in suppressing the lowering of MTT function measured as the 50%inhibitory concentration (IC50), the measured result obtained was 12 μM.

Example 2 Action in Suppressing Long-Term Potentiation Inhibition

The method for testing the suppression of the impairment of long-termpotentiation was based on that described in J. Neurosci. Vol. 20,2003-10 (2000). That is to say, acute^(i) sections of thickness 400 μmwere prepared from the hippocampus of the brains of 3-4 week old maleWistar rats. These acute sections were immersed in artificialcerebrospinal fluid in which β-amyloid protein (Aβ1-42: produced by theSigma Chemical Co.) and compound from Production Examples 1 or 12 hadbeen dissolved, and pretreatment carried out for 5 hours.

In the measurement using the compound from Production Example 1, theconcentration of the Aβ1-42 in the artificial cerebrospinal fluid was500 nM and the concentration of the compound from Production Example 1was 1 μg/mL. In the measurement using the compound from ProductionExample 12, the concentration of the Aβ1-42 in the artificialcerebrospinal fluid was 1 μM and the concentration of the compound fromProduction Example 12 was 3 μg/mL. Now, the Aβ1-42 was used aftercoagulation of the amyloid by leaving overnight.

100 pulses of high frequency stimulation at 100 Hz were applied to thepretreated acute sections, and the field excitatory postsynapticpotential: fEPSP) measured by an extracellular recording method.

The fEPSP was measured at 30 second intervals following application ofthe high frequency stimulation and the fEPSP slope (units [%]) measured.The average values of the slope over 0-20 minutes, 20-40 minutes and40-60 minutes were determined. This test was repeated five times over.The results are shown in Table 7. In the table, the figures are theaverage values ±standard deviation for the five averages obtained in thefive tests. “Test 1” shows the measurements employing the compound fromProduction Example 1 and “Test 2” shows the measurements employing thecompound from Production Example 12. “Aβ” denotes the Aβ1-42.

As controls, measurements were made of the fEPSP [mV] under the sameconditions for acute sections pretreated with the artificialcerebrospinal fluid alone, acute sections pretreated with the artificialcerebrospinal fluid in which Aβ1-42 had been dissolved, and acutesections pretreated with artificial cerebrospinal fluid in which onlythe compound from Production Example 1 or 12 had been dissolved, andthen the average value of the fEPSP slope [%] obtained.

TABLE 7 Value of fEPSP Slope [%] 0-20 20-40 40-60 minutes minutesminutes Test 1 Control group 158.8 ± 5.2 157.5 ± 4.2 155.6 ± 5.4 Aβ (500nM) 145.8 ± 5.8 136.1 ± 4.0 113.0 ± 2.6 Prod. Ex. 1 compound* 155.3 ±3.4 156.5 ± 3.9 155.8 ± 5.0 (1 μg/mL) Aβ(500 nM) + Prod. Ex. 1 150.0 ±8.4 149.6 ± 6.9 151.2 ± 7.5 compound (1 μg/mL) Test 2 Control group145.8 ± 5.8 136.1 ± 4.0 113.0 ± 2.6 Aβ (1 μM) 132.3 ± 8.8 114.4 ± 6.4103.7 ± 5.4 Prod. Ex. 12 compound** 175.3 ± 7.4 162.9 ± 9.8  160.8 ±10.3 (3 μg/mL) Aβ(1 μM) + Prod. Ex. 12 161.7 ± 2.6 148.1 ± 3.1 146.2 ±4.6 compound (3 μg/mL) Notes: *Prod. Ex. 1 compound = compound fromProduction Example 1 **Prod. Ex. 12 compound = compound from ProductionExample 12

In the control group, by applying high frequency stimulation, anincrease in the synapse transmission was confirmed over a 60 minuteperiod. However, in the group where the sections had been pretreated for5 hours with Aβ1-42, while long-term potentiation was induced itsmaintenance was impaired.

In contrast, by pretreating for 5 hours with Aβ1-42 together with thecompound synthesized in Production Example 1 or in Production Example12, which is inactive on its own, the impairment of the LTP due to theAβ1-42 was suppressed.

As can be seen in Table 7, the compounds of the present invention showan outstanding suppression action against the impairment of synapsetransmission produced by Aβ.

Average values of the fEPSP slope [%] were determined in the same way asin the test method described above, for4-(7-hydroxy-2,4,4-trimethyl-chroman-4-yl)benzene-1,3-diol (Compound Ain the table). The measured values obtained are shown below.

TABLE 8 Value of fEPSP Slope [%] 0-20 20-40 40-60 minutes minutesminutes Control group 158.7 ± 5.1 157.5 ± 4.1 155.5 ± 5.3 Aβ (1 μM)133.5 ± 9.5 123.8 ± 6.6 122.8 ± 7.1 Compound A  168.6 ± 13.0  146.6 ±15.9  149.7 ± 16.1 (1 g/mL) Aβ(1 μM) + 159.5 ± 6.6 142.8 ± 5.4 137.3 ±4.5 Compound A (1 μg/mL)

Example 3 Aβ Fibril-Formation Inhibiting Action and Fibrillar AβBreakdown Action

The Aβ fibril-formation inhibiting action and fibrillar Aβ breakdownaction were evaluated using the thioflavin binding assay method. Thedetails of the test method are based on the method described in J. Biol.Chem. Vol. 274, 25945-25952 (1999).

In the measurement of the inhibition of Aβ fibril-formation, theconcentration of the Aβ1-42 was 25 μM and the concentration of thecompound synthesized in Production Example 4 or Production Example 12was 100 μg/mL in each case. The measurement of the Aβ fibril-formationinhibiting action was carried out following incubation for 2 days at 37°C. of the Aβ1-42 alone and of the Aβ1-42 to which the compoundsynthesized in Production Example 4 or Production Example 12 had beenadded.

In the measurement of the fibrillar Aβ breakdown action, theconcentration of the Aβ1-42 was 25 μM and the concentration of thecompound synthesized in Production Example 4 or Production Example 12was 100 μg/mL in each case. After incubating the Aβ1-42 for 2 days or 3days at 37° C., the compound synthesized in Production Example 4 orProduction Example 12 was or was not added, and then further incubationperformed for 2 days, after which measurement of the fibrillar Aβbreakdown action was performed.

The measurements of the Aβ fibril-formation inhibiting action and of thefibrillar Aβ breakdown action were carried out by placing a 100 μLsample obtained by pretreatment as described above, plus 800 μL ofdistilled water, 1 mL of glycine (100 mM) and 50 μL of thioflavin (100μM) in a cuvette, and measuring the fluorescence at an excitationwavelength of 435 nm and a fluorescence wavelength of 490 nm.

The results are shown in Table 9. The figures in the table show thecalculated percentages taking the fluorescent intensity obtained whenthe fluorescence of the sample obtained by incubating Aβ1-42 (25 μM)alone by the above method, and measured at an excitation wavelength of435 nm and a fluorescence wavelength of 490 nm, was taken as 100. Thefigures are in the form of the average value ±standard deviation, forthe three to nine averages obtained in three to nine tests. In thetable, “Test 3” shows the measurements using the compound fromProduction Example 4, and “Test 4” shows the measurements using thecompound from Production Example 12. “Aβ” is for the Aβ1-42.

TABLE 9 fibril-formation fibrillar inhibiting action breakdown action(fluorescent (fluorescent intensity %) intensity %) Test 3 Aβ (25 μM)100.00 ± 1.18 100.00 ± 8.88 Aβ(25 μM) + Prod. Ex. 4  16.26 ± 5.30  30.63± 1.26 compound* (100 μg/mL) Test 4 Aβ (25 μM) 100.00 ± 2.24 100.00 ±2.07 Aβ(25 μM) + Prod. Ex. 12   1.69 ± 1.324  28.49 ± 5.17 compound**(100 μg/mL) Notes: *Prod. Ex. 4 compound = compound from ProductionExample 4 **Prod. Ex. 12 compound = compound from Production Example 12

With Aβ by itself, strong thioflavin fluorescence was confirmed. Thisshows that Aβ forms fibrils. However, in the samples obtained by addingthe compound from Production Example 4 or from Production Example 12prior to fibril formation, there was a weakening of the thioflavinfluorescence, indicating that the Aβ fibril-formation was inhibited. Thesame results were also obtained with samples obtained by adding thecompound from Production Example 4 or Production Example 12 after fibrilformation, indicating that there was a fibrillar Aβ breakdown action.

As shown in Table 8 {sic}, as well as the compounds of the presentinvention acting to inhibit Aβ fibril-formation, it is clear that theyalso act to break down formed Aβ fibrils.

Preparation Example 1 A Powder Preparation Comprising the Compound fromProduction Example 1

When 5 g of the compound from Production Example 1, 895 g of lactose and100 g of corn starch are mixed together, a powder preparation isobtained.

Preparation Example 2 Granules Comprising the Compound from ProductionExample 1

After mixing 5 g of the compound from Production Example 1, 865 g oflactose and 100 g of hydroxypropyl cellulose of low degree ofsubstitution, 300 g of 10% aqueous hydroxypropyl cellulose solution isadded and kneading performed. The mixture is extruded and granulatedusing a granulator, and then dried to obtain a granular preparation(granules).

Preparation Example 3 Capsules of the Compound of Production Example 1

After mixing together 5 g of the compound from Production Example 1, 115g of lactose, 58 g of corn starch and 2 g of magnesium stearate using aV-shape mixer, No. 3 capsule containers are filled with 180 mgquantities of the mixture and capsules obtained.

Preparation Example 4 Tablets of the Compound of Production Example 1

After mixing together 5 g of the compound from Production Example 1, 90g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 gof magnesium stearate in a blender, tableting is carried out with atableting machine and tablets obtained.

INDUSTRIAL APPLICATION POTENTIAL

The drugs of the present invention which contain a compound of generalformula (I) are outstanding in their action in suppressing the fall inMTT reduction capacity brought about by β-amyloid protein, and ininhibiting impairment of long-term potentiation of hippocampal nervecells, so they are useful as preventatives or remedies for Alzheimer'sdisease.

The amyloid protein fibril-formation inhibitors of the present inventionare outstanding in their action in inhibiting amyloid proteinfibril-formation and in their fibrillar amyloid protein breakdownaction, so they are valuable as preventatives or remedies foramyloidosis, such as Alzheimer's disease, type 2 diabetes,immunoglobulinic amyloidosis, reactive amyloidosis, familialamyloidosis, dialysis-related amyloidosis, senile amyloidosis,cerebrovascular amyloidosis, hereditary cerebral hemorrhage withamyloidosis, Creutzfeldt-Jakob disease, bovine spongiform encephalitis(BSE), scrapie, medullary carcinoma of the thyroid, insulinoma,localized atrial amyloid, amyloidosis cutis and localized nodularamyloidosis, preferably for Alzheimer's disease, type 2 diabetes,dialysis-related amyloidosis, familial amyloidosis, Creutzfeldt-Jakobdisease and BSE, in particular for Alzheimer's disease and type 2diabetes.

Furthermore, the nitrogen-containing heteroaryl derivatives of thepresent invention and their pharmacologically permitted salts arevaluable as preventives or remedies for Alzheimer's disease ofwarm-blooded animals (in particular humans), or as amyloid proteinfibril-formation inhibitors.

1-18. (canceled)
 19. A pharmaceutical composition which contains, as an active ingredient, at least one nitrogen-containing heteroaryl compound represented by the following general formula (I)

[where R¹ and R² each independently represent a hydrogen atom or a C₁₋₆ alkyl group, Z¹ and Z² each independently represent a hydrogen atom, C₁₋₆ alkyl group, C₁₋₆ alkoxy group, halo-C₁₋₆ alkyl group or halogen atom, Z³ represents a C₁₋₆ alkoxy group, mercapto group, C₁₋₆ alkylthio group, amino group, mono- or di-C₁₋₆ alkylamino group, hydroxy group or halogen atom, Z⁴ and Z⁵ each independently represent a hydrogen atom or halogen atom, and A represents a group of formula (IV) below

(where R⁷ and R⁸ each independently represent a hydrogen atom, C₁₋₆ alkyl group, C₁₋₆ alkoxy group, mercapto group, C₁₋₆ alkylthio group, amino group or mono- or di-C₁₋₆ alkylamino group or pharmacologically permitted salt thereof.
 20. A nitrogen-containing heteroaryl derivative of the formula (V11)

[where R¹ and R² each independently represent a hydrogen atom or C₁₋₆ alkyl group, Z¹ and Z² each independently represent a hydrogen atom, C₁₋₆ alkyl group, C₁₋₆ alkoxy group, halogen atom or halo-C₁₋₆ alkyl group, Z⁴ and Z⁵ each independently represent a hydrogen atom or halogen atom, and A represents a group of formula (IV) below

(where R⁷ and R⁸ each independently represent a hydrogen atom, C₁₋₆ alkyl group, C₁₋₆ alkoxy group, mercapto group, C₁₋₆ alkylthio group, amino group or mono- or di-C₁₋₆ alkylamino group or pharmacologically permitted salts thereof.
 21. A nitrogen-containing heteroaryl derivative or pharmacologically permitted salt thereof according to claim 20, where R¹ and R² are each independently a hydrogen atom or C₁₋₂ alkyl group.
 22. A nitrogen-containing heteroaryl derivative or pharmacologically permitted salt thereof according to claim 20, where R¹ and R² are hydrogen atoms.
 23. A nitrogen-containing heteroaryl derivative or pharmacologically permitted salt thereof according to claim 20, where A is group of formula (IV) where R⁷ and R⁸ are each independently a hydrogen atom or C₁₋₂ alkyl group.
 24. A nitrogen-containing heteroaryl derivative or pharmacologically permitted salt thereof according to claim 20, where A is a group of formula (IV) where R⁷ and R⁸ are hydrogen atoms.
 25. A nitrogen-containing heteroaryl derivative or pharmacologically permitted salt thereof according to claim 20, where Z¹ and Z² are each independently a hydrogen atom or para-position fluorine atom, chlorine atom or C₁₋₂ alkyl group, the hydroxy group on the phenyl ring to which Z¹ is bonded is in the meta-position, and Z⁴ and Z⁵ are hydrogen atoms.
 26. A nitrogen-containing heteroaryl derivative or pharmacologically permitted salt thereof according to any of claim 20, where Z¹ and Z² are each independently a hydrogen atom or para-position fluorine atom, chlorine atom or C₁₋₂ alkyl group, the hydroxy group on the phenyl ring to which Z¹ is bonded is in the meta-position, and Z⁴ and Z⁵ are hydrogen atoms.
 27. A nitrogen-containing heteroaryl derivative or pharmacologically permitted salt thereof according to any of claim 20, where Z¹ and Z² are hydrogen atoms or para-position methyl groups, the hydroxy group on the phenyl ring to which Z¹ is bonded is in the meta-position, and Z⁴ and Z⁵ are hydrogen atoms.
 28. A pharmaceutical composition according to claim 19 which contains, as an active ingredient, a nitrogen-containing heteroaryl derivative as defined above, or pharmacologically permitted salt thereof.
 29. A method of treating a patient in need of therapy for an amyloidosis comprising administering to the patient a therapeutically effective amount of a composition which contains as an active ingredient at least one nitrogen-containing heteroaryl compound represented by the following general formula (I)

[where R¹ and R² each independently represent a hydrogen atom or a C₁₋₆ alkyl group, Z¹ and Z² each independently represent a hydrogen atom, C₁₋₆ alkyl group, C₁₋₆ alkoxy group, halo-C₁₋₆ alkyl group or halogen atom, Z³ represents a C₁₋₆ alkoxy group, mercapto group, C₁₋₆ alkylthio group, amino group, mono- or di-C₁₋₆ alkylamino group, hydroxy group or halogen atom, Z⁴ and Z⁵ each independently represent a hydrogen atom or a halogen atom, and A represents a group of formula (II) to (VI) below

(where R⁷ and R⁸ each independently represent a hydrogen atom, C₁₋₆ alkyl group, C₁₋₆ alkoxy group, mercapto group, C₁₋₆ alkylthio group, amino group or mono- or di-C₁₋₆ alkylamino group or a pharmacologically permitted salt thereof.
 30. A pharmaceutical composition which contains, as an active ingredient, a nitrogen-containing heteroaryl derivative according to claim 20, or pharmacologically permitted salt thereof.
 31. A method of treating a patient in need of therapy for an amyloidosis comprising administering to the patient a therapeutically effective amount of a Nitrogen-containing heteroaryl derivative represented by the following general formula (VII)

wherein R¹ and R² each independently represent a hydrogen atom or C₁₋₆ alkyl group, Z¹ and Z² each independently represent a hydrogen atom, C₁₋₆ alkyl group, C₁₋₆ alkoxy group, halogen atom or halo-C₁₋₆ alkyl group, Z⁴ and Z⁵ each independently represent a hydrogen atom or halogen atom, and A represents a group of formula (II) to (VI) below

wherein R⁷ and R⁸ each independently represent a hydrogen atom, C₁₋₆ alkyl group, C₁₋₆ alkoxy group, mercapto group, C₁₋₆ alkylthio group, amino group or mono- or di-C₁₋₆ alkylamino group or a pharmacologically permitted salt thereof.
 32. A method as claimed in claim 31 wherein the nitrogen-containing heteroaryl derivative is as defined above.
 33. A method as claimed in claim 31 wherein the amyloidosis is selected from the group consisting of Alzheimer's disease, type 2 diabetes, immunoglobulinic amyloidosis, reactive amyloidosis, familial amyloidosis, dialysis related amyoidosis, senile amyloidosis, cerebrovascular amyloidosis, hereditary cerebral haemorrhage with amyloidosis, Creutzfeldt-Jacob disease, bovine spongiform encephalitis(BSE), scrapie, medullary carcinoma of the thyroid, insulinoma, localized atrial amyloid, amyloidosis cutis, localized nodular amyloidosis and familial amyloidosis 